Orvinol and Thevinol Derivatives Useful in the Treatment of Drug and Alcohol Abuse, Depression, Anxiety, or a Compulsive Disorder

ABSTRACT

The invention provides a method of treating drug and alcohol abuse, depression, anxiety, or a compulsive disorder in a subject comprising administering to the subject a compound having formula  2 : 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined in the specification.

TECHNICAL FIELD

This invention relates to orvinol and thevinol compounds useful for thetreatment of drug and alcohol abuse. The compounds are especially usefulfor the treatment of opioid abuse, cocaine abuse, alcohol abuse andpolydrug abuse, and are useful for the prevention of relapse inrecovering addicts.

BACKGROUND

The compounds of the invention are structurally related tobuprenorphine. But, unlike buprenorphine, the compounds are mu opioidreceptor (MOPr) antagonists that do not also have significant MOPragonist activity. They share buprenorphine's antagonism at kappa opioidreceptors (KOPr) and may also have activity at the NOP/ORL-1 receptor.

Orvinols

The orvinols are a group of ring-C bridged epoxymorphinan compounds ofgeneral structure (1) which were originally synthesised by Bentley andco-workers and developed by Reckitt and Colman (Lewis et al, 1971). Themost studied members of the series are the extremely potent opiateanalgesic and animal immobilising agent etorphine (1a), the very potentopiate antagonist diprenorphine (1b) and the clinical analgesic andtreatment for opiate abuse, buprenorphine (1c).

1a: R═H, R¹═R²═Me, R³═n-Pr, R⁴═H

1b: R═H, R¹=cyclopropylmethyl, R²═R═Me, R⁴═H

1c: R═H, R¹=cyclopropylmethyl, R²═Me, R³=t-Bu, R⁴═H

1d: R═R²═R³═R⁴═H, R¹=cyclopropylmethyl

1e: R═R²═R⁴═H, R¹=cyclopropylmethyl, R³═Me

1f: R═R³═R⁴═R¹=cyclopropylmethyl, R²═Me

The orvinols and derivatives of structure 1 are described in a series ofUK Patents GB902659, GB925723, GB937214, GB969263 and GB1136214, whichdiscuss their synthesis and potential therapeutic uses as analgesics,antitussives and, in some cases, antagonists of narcotic drugs. Thepatent applications do not describe compounds in which R4 is anythingother than hydrogen. Further, the stereochemistry about C20 was notspecified. The inventors have recognised that the stereochemistry aboutC20 is in fact of utmost importance and the diastereoisomers ofstructure 1 in which R2 and R3 are interchanged have very differentpharmacological profiles.

In their publications, the inventors have described how thestructure-activity relationships in the orvinols (1, R═H) and thevinois(1, R═Me) are conventional with respect to substituents on the basicnitrogen atom and at C3, the phenolic position (Lewis and Husbands,2004), but that the effect of the nature of the substituents and thestereochemistry of C20 is of even greater significance (Lewis andHusbands, 2004). In particular, the inventors have found that there isonly a very limited range of structures which have a lack of opioidagonist activity and are therefore essentially opioid antagonists. Priorto the present invention the only compounds of structure 1 to have beenshown to lack agonist activity at opioid receptors were theN-cyclopropylmethyl (N-CPM) primary and secondary alcohols (1d, 1e, 1f)(Lewis, 1973). Thus the discovery of novel orvinols with C20 arylsubstituents that lack opioid agonist activity was both unexpected anddesirable. Though compounds having structure 1 in which R2 is aryl andR4 is H are within the generic scope of GB969,263 and GB1,136,214, suchcompounds are not exemplified within those patents.

Orvinols and thevinois of structure 1 where R2 and R3 areinterchangeably phenyl and methyl groups, R4 is H and R1 includescyclopropylmethyl, allyl, dimethylallyl and propargyl were disclosed byMarton et al (Marton et al, 1997) without any definition of opioidactivity.

Orvinols and thevinois of structure 1, where R4 is methyl, have notpreviously been disclosed, in addition, the inventors have found thatthe key Diels-Alder adduct from which the novel compounds, having R4 asmethyl, are prepared in the current invention could not be synthesizedby the standard methodology which had previously allowed the standardorvinols, having R4 as H, to be prepared (Lewis et al. 1971).

Buprenorphine in the Treatment of Drug Abuse

Buprenorphine displays a unique and complex pharmacology derived fromthe manner in which it binds to opioid receptors. Like the opiateanalgesics and the antagonists naltrexone, naloxone and nalmefene,buprenorphine's primary actions are at MOPr, but it is neither an opiateagonist like morphine, nor an antagonist like naltrexone. It isclassified as a partial MOPr agonist having the characteristics of bothan agonist or an antagonist depending on the circumstances. As an MOPrpartial agonist buprenorphine shows a ceiling to all the effectsassociated with MOPr agonism including importantly the potentiallylethal effect of respiratory depression (in overdosage) and addictionliability. The latter is also favourably affected by the kinetics ofbuprenorphine's MOPr binding which has irreversible characteristics. Thevery slow dissociation of buprenorphine from MOPr is responsible, atleast in part, for its long duration of action and the mildness of theabstinence effects when drug is withdrawn following chronicadministration. The shape of the dose-response curves forbuprenorphine's MOPr agonist effects is uniquely an inverted U-shape.This means that high doses have lesser MOPr agonist effects thanintermediate doses which produce peak effects. This applies torespiratory depression, thus further contributing to the drug'sextremely favourable acute safety profile and physical dependenceliability. The very limited MOPr agonist activity of buprenorphine athigh doses is complementary to the predominant MOPr antagonist activityat these doses.

The unique pharmacological profile of buprenorphine at MOPr wasrecognised when it was approved for the treatment of opiate abuse anddependence as an agent for detoxification and maintenance. Butbuprenorphine is also unique among drugs having significant MOPr agonistactivity in having high affinity but no efficacy at KOPr and deltaopioid receptors (DOPr), thus having only antagonist activity at thesereceptors. Not only does the lack of any KOPr agonist activity mean thatbuprenorphine avoids KOPr agonist side effects particularly dysphoriaand diuresis, but KOPr antagonism is important for its potential use intreatment of substance abuse disorders other than opiate abuse. ThusKOPr antagonism contributes to its ability to inhibit cocaineself-administration in rhesus monkeys (Mello et al, 1995) and inconcurrent opiate and cocaine addicts (Montoya et al, 2004). Preclinicalstudies also support the hypothesis that KOPr antagonists may be ofutility against cocaine. The KOPr antagonists norBNI and JDTic have beenshown to block stress-induced potentiation of cocaine place preference(McLaughlin et al, 2003) and to block footshock-induced reinstatement ofcocaine self-administration behaviour (Beardsley et al, 2005; Redila andChavkin, 2008). KOPr antagonists have also been shown, in rats, toselectively attenuate ethanol-dependent self-administration whileleaving nondependent ethanol self-administration unaffected (Walker andKoob, 2008). This appears consistent with earlier findings of a decreasein alcohol self-administration in KOR knockout mice (Kovacs et al,2005).

In addition to its binding to the three classical opioid receptorsbuprenorphine also binds as a partial agonist to the ORL-1 receptor.This receptor has a high degree of amino acid sequence homology with theclassical opioid receptors, but traditional opioids, including the opiumalkaloids and the antagonists naloxone, naltrexone and nalmefene havelow affinity for the ORL-1 receptor. The endogenous ligand for ORL-1receptors, orphanin FQ has been shown to inhibit the actions of cocaine(Korlinska et al, 2002) so that buprenorphine's ORL-1 activity could beassociated with a similar effect. Gorelick (2007) suggested that sinceit is high doses of buprenorphine that significantly reduce cocaine usein patients who are both opiate and cocaine dependent (Montoya et al,2004), it is ORL-1 receptor activation which is important for thiseffect. Buprenorphine at high doses has also been shown to inhibitethanol self administration in rats, an effect that was prevented by aselective ORL-1 antagonist (Ciccocioppo et al, 2007).

In order to unmask the KOPr antagonist (and NOP/ORL-1 agonist) activity,the MOPr agonist effect of buprenorphine must be nullified. This wasachieved by combining sublingual buprenorphine (4 mg/day) with oralnaltrexone (50 mg/day) in a study in detoxified opiate addicts. After 12weeks the combination-treated group showed a lower level of urinespositive for opiates and cocaine metabolites than the comparison groupon naltrexone (50 mg) (Gerra et al, 2006). This result, which indicateda positive contribution from buprenorphine's KOPr antagonist effect,confirmed an earlier study by Rothman et al (2000) using the same dosingregime, but without a naltrexone comparison group.

The use of naltrexone, a predominantly MOR antagonist, for relapseprevention of alcohol and opioid dependence is approved in a number ofcountries. There are mixed reports on the effectiveness of oralnaltrexone in the treatment of opioid dependence, such that a recentCochrane review did not find sufficient evidence to unequivocallysupport its use (Minozzi, 2006). More recently, sustained-releasenaltrexone has become available and the limited high quality dataavailable suggests this does have advantages over oral naltrexone,including significantly higher rates of retention in treatment(Lobmaier, 2008; Comer et al, 2006). Evidence for the efficacy ofnaltrexone in treating alcohol dependence is stronger. It has been shownto be effective over both the short and medium term in preventingrelapse, particularly when combined with psychosocial treatment(Srisurapanont and Jarusuraisin, 2008). Interestingly, the positiveeffect in preventing relapse to alcohol is maintained in individualswith dual cocaine/alcohol dependence or abuse (Srisurapanont andJarusuraisin, 2008), supporting a role for MOR antagonism in reducingalcohol intake in the polydrug using community.

The case is thus made for a potent KOPr antagonist and MOPr antagonistwith ORL-1 receptor agonist activity, i.e. buprenorphine with MOPrpartial agonism replaced by MOPr antagonism, as a treatment for abuse ofa wide spectrum of substances both individually and collectively.

SUMMARY OF INVENTION

The present invention provides a compound of formula 2, or apharmaceutically acceptable salt, prodrug or solvate thereof

in which

R is H or alkyl

R1 is alkyl, alkenyl, or cycloalkylalkyl,

R2, R4 and R5 are H or methyl

R3 is aryl or heteroaryl, either of which may be substituted orunsubstituted, except that when R4 is H then R3 may not be phenyl whenR2 is methyl, including in the diastereoisomers in which R2 and R3 areinterchanged.

At C20 R2 and R3 can be interchanged to provide the oppositestereochemistry

X is a saturated bridge (—CH2CH2—) or an unsaturated bridge (—CH═CH—)

When R is alkyl it means a short chain alkyl having four carbon atoms orless and preferably one carbon atom, i.e. methyl. R is preferably H.

In R1 above, alkyl means a chain of between two and four carbon atomsoptionally substituted, preferably a n-propyl group. Cycloalkylalkylpreferably means a cycloalkyl group of three to eight carbon atoms,preferably cyclopropyl or cyclobutyl attached to the basic nitrogen atomthrough a carbon chain of one to three carbon atoms which may beoptionally substituted, and is preferably a methylene group (—CH2), withcyclopropylmethyl (CPM) being a most preferred R1 structure. Alkenylpreferably means allyl (—CH2CH═CH2) in which any of the hydrogen atomsmay be substituted, preferably by one or more methyl groups. A preferredalkenyl group is allyl.

R3 is an aryl, especially phenyl, or heteroaryl group, especially onewith four or five carbon atoms and a sulphur or nitrogen atom, i.e.thiophenyl, pyrrolyl or pyridyl. These may be optionally substitutedwith, for example, a halogen, especially fluorine or chlorine, or ashort chain alkyl such as methyl, or an oxygen, for example hydroxyl ormethoxy. R3 is preferably phenyl, optionally substituted with one ormore of methyl, a halogen, methoxy and hydroxy.

As indicated above, when R4 is H then R3 may not be phenyl when R2 ismethyl, including in the diastereolsomers in which R2 and R3 areinterchanged. This means that when R4 is H, R3 is not phenyl when R2 ismethyl. Diastereoisomers are included, such that if the positions of R2and R3 are interchanged, the exception still applies, in other words,when R4 is H and R2 is phenyl, R3 may not be methyl.

In a preferred embodiment, R is preferably H. In that embodiment, R1 ispreferably CPM.

When R1 is CPM, especially when R is H, R3 is preferably aryl,particularly phenyl, or a substituted phenyl.

In some embodiments, R2 is preferably H. In others R2 is preferablymethyl. In some embodiments, R4 is preferably H. In others R4 ispreferably methyl. When R2 is H, R4 is preferably methyl. When R2 ismethyl, R4 is preferably H. R2 may be H when R4 is H, though, and R2 maybe methyl when R4 is methyl.

In the compounds of the invention of structure 2 R2 and R3 may beinterchanged, but as indicated in the definition of R2, one or othermust be H or Me. As mentioned previously, when R4 is H and R2 is methylthen R3 may not be phenyl and, accordingly, when the positions areinterchanged, R2 may not be phenyl when R3 is methyl.

The stereochemistry shown in structure 2 when R3 is aryl or heteroarylis preferred; however, embodiments in which R2 and R3 are interchangedare included. In particular, when the two are interchanged, a preferredembodiment includes pyridyl as R2, especially with R3 being Me and R4being H.

X may be —CH2CH2— or —CH═CH—, with —CH2CH2— being preferred. When X is—CH═CH—, R4 is preferably methyl. In addition, R2 is preferably H.

Compounds of the invention may be found in table 1, excluding BU127.

The invention also provides methods for the synthesis of the novelcompounds of structure 2 where R, R1, R2, R3, R4, R5 are as specifiedabove.

In particular, there is provided a method of synthesising a compound,especially a compound of the invention, or an Intermediate for use insynthesising the compounds of the invention, the method comprising thestep of combining an N-acylnorthebaine with methacrolein in the presenceof a Lewis acid catalyst. Standard methods without Lewis acid catalystfailed to give the desired compound.

The method of synthesising a compound is preferably a method ofsynthesising an intermediate for use in synthesising a compound of theinvention. The intermediate may be aN-acyl-7alpha-formyl-7beta-methyl-6,14-endothenotetrahydronorthebaine.

Lewis acid catalysts are well known in the art. It is particularlypreferred that the Lewis acid catalyst is LiBF₄, though BF₃, OEt₂andNbCl₅ may also be used.

The invention also provides a composition comprising a compound offormula 2, or a pharmaceutical acceptable salt, prodrug or solvatethereof and a pharmaceutical acceptable excipient or carrier,

in which

R is H or alkyl

R1 is alkyl, alkenyl, cycloalkylalkyl R2, R4 and R5 are H or methyl

R3 is aryl or heteroaryl either of which may be substituted orunsubstituted and

X is a saturated bridge (—CH2CH2—) or an unsaturated bridge (—CH═CH—)

R, R1, R2, R3, R4 and R5 are preferably as defined above in relation tocompounds of the invention. The compound to be administered includes thediastereoisomers in which R2 and R3 are interchanged.

It is preferred that when R4 is H then R3 may not be phenyl when R2 ismethyl, including in the diastereoisomers in which R2 and R3 areinterchanged.

Pharmaceutical compositions of this invention comprise any of themolecules of the present invention, and pharmaceutically acceptablesalts thereof, with any pharmaceutically acceptable carrier, adjuvant orvehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions include, but are notlimited to, ion exchangers, alumina, aluminium stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic add, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulphate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers,polyethylene glycol and wool fat.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. Preferably, thepharmaceutical compositions are administered orally or by injection. Thepharmaceutical compositions may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques. Preferably, the route of administration of thecomposition is transdermal or intrathecal administration.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as Ph. Helv or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavouring and/or colouring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a molecule of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the molecules of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilising or dispersing agents known inthe art.

The composition may also comprise a second active agent or may be foradministration with another active agent, such as an NOP agonist oropioid antagonist.

Further is provided a method of treating a substance abuse disordercomprising administering an effective amount of a compound havingstructure 2 as shown above, in which

R is H or alkyl

R1 is alkyl, alkenyl, cycloalkylalkyl

R2, R4 and R5 are H or methyl

R3 is aryl or heteroaryl either of which may be substituted orunsubstituted, and X is a saturated bridge (—CH2CH2—) or an unsaturatedbridge (—CH═CH—); or a composition comprising such a compound to asubject in need thereof.

R, R1, R2, R3, R4 and R5 are preferably as defined above in relation tocompounds of the invention. The compound to be administered includes thediastereoisomers in which R2 and R3 are interchanged.

It is preferred that when R4 is H then R3 may not be phenyl when R2 ismethyl, including in the diastereoisomers in which R2 and R3 areinterchanged.

The method of treating the substance abuse disorder may comprise asingle administration of the compound or composition, or repeatedadministrations thereof. The invention also provides a compound offormula 2, or a pharmaceutically acceptable salt, prodrug or solvatethereof

in which

R is H or alkyl

R1 is alkyl, alkenyl, cycloalkylalkyl,

R2, R4 and R5 are H or methyl

R3 is aryl or heteroaryl either of which may be substituted orunsubstituted and

X is a saturated bridge (—CH2CH2—) or an unsaturated bridge (—CH═CH—),for use in therapy, especially in the treatment of a substance abusedisorder.

R, R1, R2, R3, R4 and R5 are preferably as defined in relation to themethod of treatment of the invention.

A substance abuse disorder is preferably as opiate use, particularly asa relapse prevention agent, alcohol dependence and excessive alcoholuse, cocaine use, stimulant use, polydrug abuse, and nicotine use. Inparticular it relates to opiate use in recovering addicts. It isparticularly preferred that the composition is useful for the treatmentof a substance abuse disorder, especially opiate use without the need toco-administer another MOPr antagonist.

The compound may also be useful for the treatment of depression, anxietyand compulsive disorders, e.g. gambling. A combination of buprenorphineand naltrexone, the effects of which are mimicked by the compounds ofthe invention, has been indicated to have efficacy against a number ofpsychiatric disorders such as anxiety and depression. Accordingly, thecompounds of the invention can also be used to treat such disorders.

The invention will now be described in detail, by way of example only.

EXPERIMENTAL

The compounds can be prepared by, for example, the methods outlined inSchemes 1, 2, 3 and 4. These methods are illustrative of how secondaryand tertiary alcohols are made in these series. The exact order of somethe chemical steps may be varied (for example, when the nitrogensubstituent is introduced).

The compounds (structure 2), having R4═H, can be prepared as shown inSchemes 1 and 2 fromN-cyclopropylmethyl-6,14-endoetheno-7-acetyltetrahydronorthebaine (5b)or N-cyclopropylmethyl-6,14-endoetheno-7-formyltetrahydronorthebaine(8b) by methods analogous to those described in British PatentsGB969.263 and GB1.136.214. Thus the synthesis of series 1, withstereochemistry at C20 as depicted in 7, is shown in Scheme 1, with theequivalent compounds with opposite stereochemistry at C20 (Series 2,structure 15) shown in scheme 2. However an exception was found in thecase of the synthesis of the C20-pryridyl analogues where instead ofGrignard reagent the more reactive pyridyl lithium reagents had to beused. The result was that the predominant product had thestereochemistry of structure 15a instead of the expected structure 7a.

The compounds of the invention, having R4═Me, are most readily preparedfrom N-cyclopropylcarbonyl northebaine (16) by a Diels-Alder reactionwith methacrolein to give 17a and 17b. Addition of an aryl Grignardreagent to 17b provides secondary alcohols 18 and these can be convertedto the diasteriomeric alcohols 20 by oxidation and reduction. Theorvinol analogues 22 and 23 are then made by 3-O-demethylation usingKOH, PrSNa or L-selectride (Scheme 3)

Ethano bridged analogues are prepared by catalytic hydrogenation ofadduct 17b and then equivalent chemistry to that described for theetheno series. (Scheme 4)

Experimental Data on Compounds

General Procedure A: Grignard Addition (Schemes 1 and 2)

The Grignard reagents were prepared form the corresponding bromides (5mmol) by reaction with magnesium (182 mg, 7.5 mmol) in anhydrous THF (5ml) containing a crystal of iodine). The Grignard reagents were titratedprior to use by adding 1 ml of the Grignard solution to a flaskcontaining 1,10-phenanthroline (˜2 mg) in anhydrous THF (2 ml) (purplesolution) and titrating with 1M 2-butanol (anhydrous) in THF (end pointpale yellow solution)]

Grignard reagent (1 M in THF, 1.2 ml, 1.2 mmol) was treated dropwise atroom temperature with a solution of 5 (500 mg) or 8 (500 mg) inanhydrous toluene (12 ml). After stirring at room temperature for 20 h,the reaction was quenched by addition of saturated aqueous ammoniumchloride solution (20 ml). The phases were separated and the aqueousphase extracted with EtOAc. The combined organic phases were washed withsaturated aqueous sodium bicarbonate, dried over MgSO₄, filtered andevaporated in vacuo. The residue was purified by column chromatographyover silica gel eluting with a gradient from 10% to 30% ethyl acetate inhexane. R_(f) values are recorded from TLC eluted with 30:1:69 ethylacetate/ammonia solution/hexane.

General Procedure B. Grignard Addition (Schemes 3 and 4)

To a solution of aldehyde 17b or 24 in dry THF (10 mL/mmol of aldehyde)were added 3 eq of Bu₄NBr followed by 2 eq of arylmagnesium halide assolution in THF. The solution was then heated at reflux for 48 h, cooledto RT and quenched with 0.05 mL of water. The mixture was allowed tostir for 5 min then filtered over Celite. The solids were washed withhot THF, and the solution was removed of its solvent by rotaryevaporation. The remaining residue was partitioned between EtOAc (20 mL)and water (10 mL). The water layer was extracted twice with 5 mL ofEtOAc. The pooled organic solvent was washed twice with 5 mL of water,once with brine, dried over MgSO₄, filtered and dried under reducedpressure. The residue was dissolved in a minimum amount of Et₂O toinduce crystallization. The crystals were collected by filtration, anddried under vacuum.

General Procedure C. Swern Oxidation:

A solution of oxalyl chloride (1.25 eq) in CH₂Cl₂ (3 mL/mmol) was cooledto −78° C. in a one neck flask. Into this flask was added dropwise, asolution of dry DMSO (2.6 eq) in CH₂Cl₂ (3 mL/mmol). The solutionstirred for 5 min and then a solution 9, 18 or 25 in CH₂Cl₂ (2 mL/mmol)was added. The mixture stirred for 20 min and then Et₃N (5 eq) wasadded. The reaction was removed from the cold bath, stirred for 1 h andwater was added. The mixture was shaken, the organic layer was separatedand washed with a saturated solution of NH₄Cl, then with a concentratedsolution of NaHCO₃. The solution was washed once more with brine, driedover magnesium sulfate, filtered, and the solvents removed under reducedpressure to yield crude 11, 19 or 26 as a clear residue.

General Procedure D. LiAlH₄ Reduction

Substrate (11, 18, 19, 25 or 26) was dissolved in dry THF (10 mL/mmol)and added to a stirring suspension of LiAlH₄ (4 eq) in dry THF (5mL/mmol) at 0° C. The suspension was allowed to warm up to RT and wasstirred for 24 h. The reaction was cooled to 0° C. and quenched withwater in THF. The mixture was filtered, rinsing the solids with hot THF.The solution was subjected to rotary evaporation to yield an oil thatwas subjected to silica gel column chromatography eluting with 15% EtOAcin petroleum ether to yield product.

General Procedure E. O-Demethylation using NaSPr/HMPA:

A solution of 6, 9, 12, 14, 20, 21, 27 or 28 in dry HMPA (6 mL/mmol) wasadded sodium propanethiolate (6 eq). The reaction was stirred for 3 h at115 then cooled to RT and quenched with 7 mL/mmol of a concentratedsolution of NH₄Cl. The mixture was extracted three times with Et₂ 0. Theorganic layer was then extracted five times with water, once with brine,dried over MgSO₄, filtered and the solvents were removed under reducedpressure. The residue was then subjected to silica gel flash columnchromatography eluting with a gradient of EtOAc in petroleum ether. Thefractions containing the compound of Interest were then evaporated todryness and dissolved in a 2 M solution of HCl in EtOH, and then inducedto crystallize upon addition of EtOAc. The crystals were collected byfiltration, and dried under vacuum.

General Procedure F. O-Demethylation using L-Selectride:

L-Selectride® in THF (5 equivalents of a 1M solution) was added to thestarting material (6, 9, 12, 14, 20, 21, 27 or 28) under nitrogen andthe resulting solution heated to 80° C. and stirred for 14 hours, duringwhich time a change from clear to white and opaque was observed. ExcessL-Selectride® was quenched with water and solvent removed under vacuum.The resulting residue was extracted into dichloromethane, washed withdistilled water and saturated brine solution, dried (MgSO₄) and solventsagain removed under vacuum.

N-Cylcopropylmethyl-6,14-endo-ethanonorthevinone (5a) [Marton et al1997]

A solution of 4a (6 g, 14.8 mmol) in anhydrous DMF (36 ml) was treatedsequentially at room temperature with sodium bicarbonate (5 g, 60 mmol)and (bromomethyl)cyclopropane (1.87 ml, 19.3 mmol). The resultingsuspension was heated to 90° C. and stirred for 20 h. On cooling, theDMF was removed in vacuo and the residue dissolved in water and renderedbasic with 2 M NaOH solution. The product was extracted into chloroformand the organic phases washed with brine, dried over MgSO₄, filtered andevaporated to dryness. The resulting yellow solid was purified by columnchromatography over silica gel (50% ethyl acetate in hexane, R_(f)=0.50)affording 6.15 g 5a as a white solid (98%). Mp 105-106° C. 1H NMR (270MHz, CDCl₃) δ 0.04-0.10 (2H, m), 0.43-0.49 (2H. m), 0.63-0.80 (1H, m),1.22-1.34 (1H, m), 1.49-1.75 (4H, m), 1.96-2.08 (1H, m), 2.20-2.38 (4H,m), 2,25 (3H, s), 2.58-2.77 (2H, m), 2.93-3.11 (3H, m), 3.42 (3H, s),3.86 (3H, s), 4.47 (1H, s), 6.55 (1H, d, J=8.0 Hz), 6.63 (1H, d, 8.0Hz). ¹³C NMR (68 MHz, CDCl₃) δ 3.4, 4.2, 9.6, 17.6, 22.8, 28.8, 30.5,33.9, 35.4, 35.5, 43.8, 46.6. 49.8, 52.4, 56.8, 58.4, 59.9, 77.8, 94.8,113.9, 119.2, 128.9, 132.8, 141.8, 146.8. 211.1. HRMS (ESP) calcd forC₂₆H₃₄NO₄ (MH⁺), 424.2488; found 424.2485.

N-Cyclopropylmethyl-6,14-dihydronorthevinal (8a) andN-cyclopropylmethylnorthevinal (8b)

N-CPMnorthebaine (3) (1 equlv.) and acrolein (1.2 equiv.) were heated toreflux in toluene (4 mL/mmol) overnight. The solvent and excessdienophile were removed in vacuo and the product purified by silica gelchromatography (8b: 74%), Rf (EtPAc:NH4OH, 99.5:0.5) 0.58, . ¹H NMR (270MHz, CDCl₃) δ (0.14(2H, m), 0.50 (2H, m), 0.83 (1H, m), 1.45 (1H, dd),2.98 (1H, dd), 3.11 (1H, d), 3.57 (1H, d), 3.62 (3H, s), 3.82 (3H, s),4.64 (1H, d), 5.59 (1H, d), 5.89 (1H, d), 6.52 (1H, d), 6.62 (1H, d),9.43 (1H, d); ¹³C NMR (68 MHz, CDCl₃) δ 3.43, 4.17, 9.44, 23.21, 26.76,33.45, 42,92, 43.97, 48.05, 49.87, 52.70, 56.56, 57.11, 59.80, 80.92,93.62, 113.39, 119.51, 126.47, 128.15, 133.96, 137.45, 141.93, 147.93,201.96; LRMS (El) 407 (M⁺), HRMS found 407.2096, C₂₅H₂₉NO₄ requires407.2097.

This adduct 8b (6.0 g, 14.7 mmol) was dissolved in EtOH (45 mL) andtreated with 10% Pd/C (60 mg) under a H₂ atmosphere at 65 psi at 50° C.for 24 h. After cooling to rt the catalyst was removed by filtrationthrough Celite and the solvent removed in vacuo. 5.9 g (8a: 98%), Rf(Hexane: EtOAc: NH₄OH, 33:66:1) 0.48; . ¹H NMR (270 MHz, CDCl₃) δ 0.09(2H, m), 0.49 (2H, m), 0.76 (1H, m), 3.00 (1H, d), 3.51 (3H, s), 3.87(3H, s), 4.58 (1H, d), 6.58 (1H, d), 6.72 (1H, d), 9.92 (1H, d); ¹³C NMR(68 MHz, CDCl₃) δ 3.40, 4.11, 9.46, 19.95, 22.79, 26.72, 28.64, 35.33,35.46, 43.70, 46.02, 48.80, 51.67, 56.68, 58.45, 59.86, 77.37, 92.37,113.86, 119.10, 119.32, 128.58, 132.39, 141.82, 203.33; m/z (El) 409(M⁺); HRMS (El) found 409.2263, C₂₅H₃₁NO₄ requires 409.2253.

Series 1, Scheme 1: R=Ph (1′S, 5α, 6R, 7R,14α)-1,-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphinan-7-yl)-ethan-1′-ol(BU127) 5 was treated as in procedure A with phenylmagnesium bromidefollowed by procedure E or F. White solid, (Rf=0.21; 0.5% NH₄OH, 30%EtOAc in hexane; column ran in 30% EtOAc in hexane). 1H NMR (400 MHz,CDCl₃) δ −0.10-0.00 (2H, m), 0.31-0.42 (2H, m), 0.55-0.62 (1H, m),0.69-0.77 (1H, m), 0.91 (1H, dd, J=13.5 and 9.5 Hz), 1.02-1.10 (1H, m),1.58 (1H, dd, J=12.5 and 2.5 Hz), 1.76-1.90 (3H, m), 1.80 (3H, s),1.94-2.02 (1H, m), 2.10-2.20 (5H, m), 2.45 (1H, dd, J=11.5 and 5.0 Hz),2.85-2.93 (2H, m), 3.57 (3H, s), 4.45 (1H, d, J=2.0 Hz), 5.49 (1H, s),6.48 (1H, d, 7=8.0 Hz), 6.66 (1H, d, J=8.0 Hz), 7.23-7.26 (1H, m),7.32-7.36 (2H, m), 7.51-7.53 (2H, m). 13C NMR (100.6 MHz, CDCl₃) δ 3.3,4.2, 9.4, 18.0, 22.9, 23.7, 30.0, 32.7, 35.6. 36.2, 43.6, 47.3. 48.5,52.9, 58.1, 59.6, 77.5, 80.9, 97.6, 116.4, 119.7, 126.2, 126.9, 128.0,128.5, 132.5, 137.3, 145.5, 147.2. HRMS (ESI⁺) calcd for C₃₁H₃₈NO₄(MH⁺), 488.2795; found 488.2794 (100%).

Series 1, Scheme 1, R=2-thienyl: (1′S, 5α, 6R, 7R,14α)-1′-(2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphinan-7-yl)-ethan-1′-ol(BU08026)

5 was treated as in procedure A with 2-thienyl magnesiumbromide followedby procedure E or F. Rf (30% EtoAc-Pet.Ether-0.5%NH₃) 0.5. δ_(H) (270MHz; CDCl₃) 7.2 (1H, d, J 4.2,1×2-thienyl.CH), 6.9 (1H, t, J 3.6,1×2-thienyl.CH), 6.9 (1H,d, J 4.9, 1×2-thienyl.CH). 6.7 (1H, d, J 8.2,CH), 6.5 (1H, d, J 8.9, CH), 5.8 (1H, s, 21-OH), 4.4 (1H, s, 5α-H), 3.9(3H, s, 3-OCH₃), 3.6 (3H, s, 6-OCH₃), 2.9 (1H, d, J 19.0, 10β-H), 2.9(1H, d, J 7.2, 9 α-H), 0.6-0.7 (1H, m, N—CH₂CH(CH₂—CH₂—)), 0.3-0.4 (2H,m, N—CH₂CH(CH₂—CH₂—)), 0 (2H, m, N—CH₂CH(CH₂—CH₂—)).

By a similar method the following ligands were prepared:

Series 1, Scheme 1, R=m-tolyl: (1′S, 5α, 6R, 7R,14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphlnan-7-yl)-ethan-1′-ol(BU10092)

Rf (30% EtoAc-Pet.Ether-0.5% NH3) 0.8. δ_(H) (270 MHz; CDCl₃) 7.5-7.6(1H, m, 4×aryl.CH), 7.1 (3H, d, J 3.3, 2-methylphenyl), 6.7 (1H, d, J8.3, CH). 6.6 (1H, d, J 8.2, CH), 5.9 (1H, s, 21-OH), 4.4 (1H. s. 5α-H),3.9 (3H, s, 3-OCH₃), 3.3 (3H, s, 6-OCH₃), 2.9 (2H, d, J 19.0, 10β-H),2.9 (1H, d, J 7.2, 9α-H), 0.6-0.7 (1H, m, N—CH₂CH(CH₂—CH₂—)), 0.3-0.4(2H, m, N—CH₂CH(CH₂—CH₂—)), −0.1-0 (2H, m, N—CH₂CH(CH₂—CH₂—)).

Series 1, Scheme 1, R=p-t-butylphenyl: (1′S, 5α, 6R, 7R,14α)-1′-(4″-t-butylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU08024)

Rf 0.33 ¹H NMR (400 MHz, CDCl₃) δ −0.07 (2H, m), 0.31-0.33 (2H, d, J=8.0Hz), 068-072 (1H, m), 0.73-0.86 (1H, m), 0.86-0.92 (1H, m), 0.99-1.03(1H. m), 1.31 (10H, s), 1.52-1.55 (1H, d, J=12.5 Hz), 1.77 (5H, s),1.81-1.84 (1H, m), 2.03-2.10 (1H, m), 2.13-2.20 (5H, m), 2.46-2.48 (1H,m), 2.77-278 (1H, m), 2.87-2.91 (1H, d, J=18.3 Hz), 3.54 (3H, s), 4.43(1H, s), 5.44 (1H, s), 6.44-6.46 (2H, d, J=8.0 Hz), 6.61-6.63 (2H, d,J=8.0 Hz), 7.32-7.33 (2H, d, J=4.1 Hz), 7.34 (2H, d, J=4.7 Hz); ¹³C NMR(100.6 MHz, CDCl₃) 5 3,4, 3.5, 9.1, 17.8, 23.0, 23.4, 29.8, 31.3, 32.4,34.3, 35.5, 36.0, 43.2, 47.0, 48.3, 52.7, 58.5, 59.2, 80.7, 97.2, 116.3,119.4, 124.6, 125.6, 128.1, 132.3, 137.2,144.0, 145.4,149.3; ESIMS m/z:544 [M+1]⁺.

Series 1, Scheme 1, R=p-i-propy(phenyl: (1′S, 5α, 6R, 7R,14α)-1′-(4-isopropylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10096)

¹H NMR (CDCl₃) δ −0.09-−0.04 (2H, m), 0.31-0.0.35 (2H, m), 0.57-0.60(1H, m), 0.68-0.75 (1H, m), 0.86-0.92 (1H, m), 1.00-1.05 (1H, m), 1.24(6H, d, J=6.88 Hz), 1.56 (1H, s), 1.78 (3H, s), 1.79-1.85 (3H, m),1.98-2.04 (2H, m), 2.10-2.23 (4H, m), 2.45-2.49 (1H, m), 2.78 (1H, d,J=6.40 Hz), 2.88-2.93 (2H, m), 3.56 (3H, s), 4.45 (1H, s), 4.61 (1H,bd), 5.30 (1H, bd), 6.47 (1H, d, J=8.0 Hz), 6.66 (1H, d, J-8.0 Hz), 7.17(2H, d, J-8.1 Hz), 7.40 (2H, d, J=8.1 Hz); ¹³C NMR, 400 MHz, (CDCl3) δ3.40, 3.65, 9.29, 17.92, 23.05, 23.59, 23.92, 24,12, 29.87, 32.60,33.72, 35.61, 36.16, 43.35, 47.25, 48.53, 52.71, 58.56, 59.39, 80.80,97.56, 116.22, 119.52, 125.81, 125.91, 128.51, 132.52, 137.12, 144.75,145.48, 147.14. HRMS, m/z for (C₃₄H₄₄NO₄) [MH]⁺, calcd- 530.3270, found-530.3285.

Series 1, Scheme 1, R=p-chlorophenyl: (1′S, 5α, 6Rf 7R,14α)-1′-(4-chlorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10097)

¹H NMR (CDCl₃) δ −0.03- −0.02 (2H, m), 0.37-0.0.41 (2H, m), 0.58-0.62(1H, m), 0.71-0.74 (1H, m), 0.85-0.90 (1H, m), 0.99-1.05 (1H, m). 1.54(1H, m), 1.75 (3H, s), 1.77-1.84 (3H, m), 1.99-2.05 (2H, m), 2.14-2.22(4H, m), 2.44-2.48 (1H, m), 2.86-2.90 (2H, m), 3.58 (3H, s), 4.42 (1H,s), 4.63 (1H, bd), 5.46 (1H, bd), 6.51 (1H, d, J=8.0 Hz), 6.69 (1H, d,J=8.0 Hz), 7.29 (2H, d, J=11.1 Hz), 7.43 (2H, d, J=11.1 Hz); ¹³C NMR,400 MHz, (CDCl3) 5 3.20, 4.03, 9.27, 17.83, 22.79, 23.48, 29.86, 32.60,35.59, 36.09 43.45, 47.29, 48.52, 52.81, 57.99, 59.50, 80.85, 97.48,116.32, 119.60, 127.60, 127.93, 128.49, 132.35, 132.54, 137.13, 145.44,146.10; HRMS, m/z for (C₃₁H₃₇ClNO₄): [MH]⁺; calcd 522.2411,found-522.2515

Series 1, Scheme 1, R=m-chlorophenyl: (1′S, 5α, 6R, 7R,14α)-1′-(3-chlorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10098)

¹H NMR, 400 MHz, (CDCl₃) δ −0.05- −0.02 (2H, m), 0.36-0.0.42 (2H, m),0.60-0.62 (1H, m), 0.70-0.76 (1H, m). 0.89-0.93 (1H, m). 1.02-1.07 (1H,m), 1.56 (1H, s). 1.75-1.85 (6H, m), 2.01-2.06 (2H, m), 2.15-2.23 (4H,m), 2.44-2.48 (1H, m), 2.87-2.94 (2H, m), 3.57 (3H, s), 4.43 (1H, s),4.68 (1H, s), 5.48 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.67 (1H, d,J=J=8.0 Hz), 7.21-7.28 (2H, m), 7.37 (1H, d, J=10.6 Hz), 7.53 (1H, s):¹³C NMR, 400 MHz, (CDCl₃) 6 3.21, 4.03, 9.27, 17.87, 22.84, 23.54,29.84, 32.53, 35.60, 36.10, 43.46, 47.27, 48.44, 52.81, 57.98, 59.44,80.87, 97.42,116.34, 119.62, 124.40, 126.50, 126.92, 128.47, 129.05,132.37, 133.89, 137.14, 145.44, 149.68; HRMS, m/z for (C₃₁H₃₇FNO₄)[MH]⁺; calcd 522.2411, found- 522.2447.

Series 1, Scheme 1, R=3,5-dimethylphenyl: (1′S, 5α, 6R, 7R,14α)-1′-(3,5-dimethylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10100)

¹H NMR (CDCl₃) δ −0.04-−0.01 (2H, m), 0.34-0.0.42 (2H, m), 0.61-0.65(1H, m), 0.70-0.76 (1H, m), 0.94-0.99 (1H, m), 1.04-1.11 (1H, m), 1.56(1H, s), 1.76 (3H, s), 1.79-1.86 (3H, m), 2.00-2.07 (2H, m), 2.14-2.24(4H, m), 2.33 (6H, s), 2.41-2.45 (1H, m), 2.90-2.94 (2H, m), 3.56 (3H,s), 4.45 (1H, s), 4.80 (1H, bd), 5.41 (1H, bd), 6.48 (1H, d, J=8.0 Hz),6.66 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.10 (2H, s): ¹³C NMR, 400 MHz,(CDCl₃) δ 3.00, 4.23, 9.19, 18.12, 21.59, 22.78, 23.83, 29.87, 32.53,35.52, 36,09, 43.67, 47.17, 48.16, 52.70, 57.81, 59.27, 80.87, 97.34,116.29, 119,53, 123.90, 128.29, 128.45,132.48, 136.93, 137.16, 145.47,147.41; HRMS, m/z for (C₃₃H₄₂NO₄) [MH]⁺: calcd 516.3114, found- 516.3145

Series 1, Scheme 1, R=o-tolyl: (1′S, 5α, 6Rf 7R,14α)-1,-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethy1-6,14-ethanomorphinan-7-yl)-ethan-1′-ol (BU10101)

¹H NMR (CDCl₃) δ −0.08- −0.03 (2H, m), 0.31-0,0.38 (2H, m), 0.56-0.58(1H, m), 0.69-0.76 (1H, m), 0.83-0.89 (1H, m), 1.02-1.09 (1H, m),1.59-1.63 (1H, m), 1.79-1.89 (6H, m), 1.98-2.05 (1H, m), 2.13-2.23 (4H,m), 2.45-2.49 (1H, m)f 2.62-2.66 (1H, m), 2.75 (3H, s), 2.84-2.93 (2H,m), 3.56 (3H, s), 4.45 (1H, s), 4.62 (1H, bd), 5.06 (1H, bd), 6.48 (1H,d, J=8.0Hz), 6.67 (1H, d, J=8.0 Hz), 7.07-7.17 (3H, m), 7.22-7.24 (1H,m): ¹³C NMR, 400 MHz, (CDCl₃) δ 3.17, 4.06, 9.22, 18,24, 22.76, 22.84,25,93, 29.87, 32.66, 35.63, 36.11, 43.52, 43.72, 47,34, 52.68, 57.92,59.47, 79.68, 80.85 97.80, 116.27, 119.55, 124.83, 126.84, 127.50,128.56, 132.43, 132.81, 136.84, 137.11, 143.64, 145.49; HRMS, m/z for(C₃₂H₄₀NO₄). [MH]⁺, calcd- 502.2957, found-502.3017

Series 1, Scheme 1, R=4-dimethylphenyl: (1′S, 5α, 6R, 7R,14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10102)

¹H NMR (CDCl₃) δ −0.06- −0.03 (2H, m), 0.35-0.0.40 (2H, m), 0.58-0.62(1H, m), 0.70-0.76 (1H, m), 0.84-0.89 (1H, m), 0.99-1.06 (1H, m), 1.59(1H, s), 1.74-1.84 (6H, m), 1.94-2.07 (2H, m), 2.14-2.22 (4H, m),2.44-2.48 (1H, m), 2.85-2.91 (2H, m), 3.58 (3H, s), 4.44 (1H, s), 4.59(1H, s), 5.45 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=8.0 Hz),6.99-7.04 (2H, m), 7.41-7.46 (2H, m): ¹³C NMR, 400 MHz, (CDCl₃) δ 3.22,3.99, 9.27, 17.80, 22.83, 23.58, 29.86, 32.64, 35.60, 36.09, 43.45,47.29, 48.72, 52.81, 58.05, 59.48, 80.83, 97.54, 114.39, 114.60, 116.32,119.59, 126.64, 127.70, 128.47, 128.98, 132.35, 137.13, 143.35, 145.45,160.57; HRMS, m/z for (C₃₁H₃₇FNO₄), [MH]⁺: calcd 506.2707, found-506.2749

Series 1, Scheme 1, R=3-fluorophenyl: (1′S, 5α, 6R, 7R,14α)-1′-(3-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10103)

¹H NMR (CDCl₃) δ −0.05-−0.03 (2H, m), 0.35-0.0.40 (2H, m), 0.58-0.63(1H, m), 0.70-0.76 (1H, m), 0.87-0.93 (1H, m), 1.01-1.09 (1H, m), 1.60(1H, s), 1.75-1.86 (6H, m), 1.97-2.14 (2H, m), 2.17-2.22 (4H, m),2.45-2.49 (1H, m), 2.81-2.94 (2H, m), 3.58 (3H, s), 4.44 (1H, s), 4.64(1H, s), 5.45 (1H, bd), 6.48 (1H, d, J= J=8.0 Hz), 6.67 (1H, d, J=J=8.0Hz), 6.92-6.97 (1H, m), 7.24-7.29 (3H, m): ¹³C NMR, 400 MHz, (CDCl₃) δ3.28, 3.94, 9.28, 17.83, 22.85, 23.51, 29.86, 32.51, 35.60, 36.09,43.40, 47.28, 48.52, 52.81, 58.09, 59.49, 80.84, 97.48, 113.23, 113.45,113.69, 116.31, 119.61, 121.76, 128.48, 129.17, 132.38, 137.13, 145.44,150.23, 161.63; HRMS, m/z for (C₃₁H₃₇FNO₄), [MH]⁺: calcd 506.2707,found- 506.2749

Series 1, Scheme 1, R=3-methyl-2-thienyl: (1′S, 5α, 6R, 7R,14α)-1′-(3-methyl-2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10093)

Rf (30% EtOAc.Pet.Ether-0.5% NH₃) 0.17. δ_(H) (400 MHz; CDCl₃) 7.03 (1H,d, J 5.04, 1× thienyl.CH), 6.76 (1H, d, J 5.12, 1× thienyl.CH), 6.68(1H, d, J 8.04, 2-H), 6.50 (1H, d, J 8.08, 1-H), 5.30 (1H, s, 20-OH),4.51 (1H, s, 3-OH), 4.46 (1H, s, 50-H), 3.56 (3H, s, 6-OCH₃), 2.93 (1H,d, J 18.04, 10β-H), 2.90 (1H, d, J 6.36, 9α-H), 2.46-2.51 (2H, m,includes 15/16-NCH₂.CH₂—), 2.48 (3H, s, 1× thienyl.CH₃), 2.15-2.31 (5H,m, includes 7β-H, 10α-H, 15/16-NCH₂,CH₂—), 1.79-1.89 (3H, m,15/16-NCH₂,CH₂—, 2× 18/19-H), 1.87 (3H, s, 20-CH₃), 1.60-1.64 (1H, m,15/16-NCH_(2,)CH₂—), 1.04-1.10 (1H, m, 8α-H), 0.68-0.78 (1H, m,18/19-H), 0.62-0.68 (1H, m, N- CH₂CH(CH₂—CH₂—)), 0.34-0.45 (2H, m,N—CH₂CH(CH₂—CH₂—)), −0.02-0.01 (2H, m, N—CH₂CH(CH₂—CH₂—)); δ_(C)(100.56MHz; CDCl3) 145.49, 144.06, 137.18, 133.14, 132.40, 131.75,128.47, 121.22, 119.59, 116.35, 97.60, 80.53, 59.45 (NCH2CH(CH2)2),57.94, 52.78, 47.35, 43.54 (CH₂), 36.09, 35.63 (CH₂), 32.20 (CH₂), 29.84(CH₂), 25.61, 22.80 (CH₂), 21.03, 18.00 (CH₂), 16.02, 14.20, 9.30, 4.10(CH₂), 3.22 (CH₂). m/z 508 (M⁺+1), (Found M⁺+1, 508.2572. C₃₀H₃₈NO₄Srequires 508.2522).

Series 1, Scheme 1, R=p-Tolyl (1′S, 5α, 6R, 7R,14α)-1′-(4-methyl-phenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10135)

Rf (30% EtOAc.Pet, Ether-0.5% NH₃) 0.23. δ_(H) (400 MHz; CDCl₃) 7.39(2H, d, J 8.20, 2× aryl.CH), 7.14 (2H, d, J 7.92, 2× aryl.CH), 6.68 (1H,d, J 8.04, 2-H), 6.49 (1H, d, J 8.08, 1-H), 5.42 (1H, s, 20-OH), 4.62(1H, s, 3-OH), 4.51 (1H, s, 5β-H), 3.57 (3H, s, 6-OCH₃), 2.91 (1H, d, J18.88, 10β-H), 2.87 (1H, d( J 6.80, 9α-H), 2.43-2.47 (1H, m, 15/16-NCH₂,CH₂—), 2.35 (3H, s, 1× aryl.CH₃), 2.12-2.21 (4H, m, includes 7β-H,10α-H), 2.07-2.12 (1H, m, 15/16-NCH₂, CH₂—), 1.95-2.02 (1H, m,15/16-NCH₂CH₂—), 1.82-1.88 (1H, m, 15/16-NCH₂, CH₂—), 1.79-1.83 (1H, m,8β-H), 1.77 (3H, s, 20-CH₃), 1.00-1.09 (1H, m, 18/19-H), 0.87-0.93 (1H,m, 8α-H), 0.69-0.76 (1H m, 18/19-H), 0.56-0.64 (1H, m,N—CH₂CH(CH₂—CH₂—)), 0.32-0.43 (2H, m, N—CH₂CH(CH₂—CH₂—)), -0.09-0 (2H,m, N—CH₂CH(CH₂—CH₂—)); δ_(C) (100.56MHz; CDCl₃) 145.34, 137.00, 136.03,132.38, 128.45, 125.86, 119.45, 116.13, 80.71, 59.41 (NCH₂CH(CH₂)₂),57.88, 52.72, 48.30, 47.14, 43.42 (CH2), 35.97 (CH₂), 32.49, 22.64(CH2), 20.98, 17.86 (CH2), 9.17, 4.00 (CH₂), 3.13 (CH2). m/z 502 (M⁺+1),(Found M⁺+1, 502.3048. C₃₂H₄₀NaO₄ requires 502.2957).

Series 1, Scheme 1, R=5-Chloro-2-Thienyl (1′S, 5α, 6R, 7R,14α)-1′-(5-chloro-2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU10136)

Rf (30% EtOAc.Pet.Ether-0.5% NH₃) 0.12. δ_(H) (400 MHz; CDCl3) 6.72 (1H,d, J 3.80. 1× thieny.CH), 6.68 (1H, d, J 8.04, 2-H), 6.61 (1H, d, J3.84, 1× thienyl.CH), 6.50 (1H, d, J 8.08, 1-H), 5.69 (1H, s, 20-OH),4.56 (1H, s, 3-OH), 4.42 (1H, s, 5β-H), 3.57 (3H, s, 6-OCH₃), 2.94 (1H,d, J 18.56, 10β-H), 2.90 (1H, d, J 6.52, 9α-H), 2.52-2.57 (1H, m,15/16-NCH₂, CH₂—), 2.15-2.35 (5H, m, includes 7β-H, 10α-H, 15/16-NCH₂,CH₂—), 1.77-1.88 (3H, m, 15/16-NCH₂, CH₂—), 2×18/19-H), 1.76 (3H, s,20-CH₃). 1.59-1.63 (1H, m, 15/16-NCH₂, CH₂—), 1.00-1.10 (1H, m,18/19-H), 0.86-0.95 (1H, m, 8α-H), 0.67-0.77 (2H, m, 18/19-H,N—CH₂CH(CH₂—CH₂—)). 0.36-0.47 (2H, m, N—CH₂CH(CH₂—CH₂—)), −0.04-0.06(2H, m, N—CH₂CH(CH₂—CH₂—)); δ₅C (100.56MHz; CDCl₃) 151.81, 146.75,141.55, 132.47, 129.06, 128.80, 124.93, 122.13, 119.10, 113.84, 96.91,80.65, 59.52 (NCH₂CH(CH₂)₂), 57.84, 56.76, 52.99, 49.40,47.00, 43.37(CH₂), 35.90, 35.53 (GHz), 32.59 (CH₂), 29.81 (CH₂), 23.41, 22.55 (CH₂),17,69 (CH₂), 9.27, 4.07 (CH₂), 3.25 (CH₂). m/z550 (M⁺+Na), (Found M⁺+Na,550.1774. C₂₉H₃₄CINNaO₄S requires 550.1795).

Series 1, Scheme 1, R=3-Thienyl (1′S, 5α, 6R, 7R,14α)-1′-(3-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU11001)

Rf (30% EtOAc.Pet.Ether-0.5% NH₃) 0.11, δ_(H) (400 MHz; CDCl₃) 7.26 (1H,d, J 2.96, 1× thienyl.CH), 7.20 (1H, d, J 5.00, 1× thienyl.CH), 7.16(1H, d, J 2.88, 1× thienyl.CH), 6.68 (1H, d, J 8.04, 2-H), 6.50 (1H, d,J 8.00, 1-H), 5.32 (1H, s, 20-OH), 4.59 (1H, s, 3-OH), 4.46 (1H, s,5β-H), 3.58 (3H, s, 6-OCH₃), 2.93 (1H, d, J 18.40, 10β-H), 2.86 (1H, d,J 6.16, 9α-H), 2.49-2.53 (1H, m, 15/16-NCH₂, CH₂—), 2.12-2.28 (6H, m,7β-H, 8β-H, 10a-H, 15/16-NCH2.CH2-), 1.81-1.92 (3H, m, 15/16-NCH2, CH₂—,2×18/19-H), 1.79 (3H, s, 20-CH₃), 1.58-1.63 (1H, m, 15/16-NCH₂, CH₂—),1.04-1.07 (1H, m, 18/19-H), 0.89-0.97 (1H, m, 8α-H), 0.70-0.80 (1H, m,18/19-H), 0.60-0.70 (1H, m, N—CH₂CH(CH₂—CH₂—)), 0.34-0.45 (2H, m,N—CH₂CH(CH₂—CH₂—)), -0.06-0.03 (2H, m, N—CH₂CH(CH₂—CH₂—)); δ_(c)(100.56MHz; CDCl₃) 149.44, 137.04, 126.37, 124.94, 120.41, 119.48,116.18, 97.52, 80.63, 59.47 (NCH₂CH(CH2)₂), 58.22, 52.67, 48.22, 47.29,43.33 (CH₂), 36.05, 35.57 (CH₂), 32.47 (CH₂), 29.76 (CH₂), 23.90, 22.85(CH₂), 17.79 (CH₂), 9.27, 3.79 (CH₂), 3.28 (CH₂). m/z 494 (M⁺+1), (FoundM⁺+1, 494.2411. C₂₉H₃₆NO₄S requires 494.2365).

Series 1, Scheme 2, R=Ph: (1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU147)

Using General Procedure A with methylmagnesium bromide on ketone 11a(R=Ph), followed by General Procedure E or F. White solid. R_(f)=0.5(MeOH:DCM, 1:10); ¹H NMR (270MHz, CDCl₃)δ 0.10 (2H, m), 0.51 (2H, m),0.84 (1H, m), 1.55 (3H, s), 2.92 (1H, d), 2.95 (1H, d), 3.41 (3H, s),4.33 (1H, d), 6.03 (1H, s), 6.41 (1H, d), 6.58 (1H, d), 7.25 (3h, m),7.55 (2H, m); ¹³C NMR (68 MHz, CDCl₃) δ 3.90, 4.12, 9.73, 15.72, 22.97,29.15, 31.02, 31.28, 35.80, 36.09, 43.98. 47.01, 49.94, 52.73, 59.02,60.39, 80.86, 98.33, 116.73, 119.67, 126.90, 126.98, 127.70, 128.48,132.79, 137.81, 145.98,146.56. HRMS (EI) calcd for C₃₁H₄₄NO₄ (M⁺),487.2723; found 487.2323.

Series 2, R=2-pyridyl: (1′R, 5α, 6R, 7R,14α)-1′-(2-pyridyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU11005)

2-Bromopyridine (0.11 ml, 0.1.13 mmol) was taken in dry diethylether andsolution was cooled to −78° C. with dry ice under nitrogen atmosphere.Thereafter a solution of n-butyllithium (1.13 mmol) was dropwise addedto it. The reaction mixture was stirred for 10 min. then 5a dissolved indry THF was added to it. The reaction mixture was allowed to warm toroom temperature and stirred for 20 h. After completion, the reactionmixture was quenched with saturated ammonium chloride solution (aqueous)and extracted with ethylacetate. Organic layer was washed with brine,dried over sodium sulfate and vacuum evaporated to obtained crudeproduct which was purified by flash chromatography usingmethanol:dichloromethane (0.5:99.5). White Solid; ¹H NMR (CDCl₃) δ0.08-0.11 (2H, m), 0.40-0.51 (2H, m), 0.80-0.88 (2H, m), 1.20-1.27 (2H,m), 1.62 (1H, d, J=2.68 Hz), 1.67 (3H, s), 2.02-2.41 (8H, m), 2.61 (1H,dd, J-11.72, J=5.12 Hz), 2.78 (1H, dt, J-112.16, J=3.92 Hz), 2.91 (1H,d, J=18.24 Hz), 3.02 (1H, d, J-6.40 Hz), 3.35 (3H. s), 4.39 (1H, s),4.55 (1H, bd), 5.83 (1H, s), 6.43 (1H, d, J=8.0 Hz), 6.61 (1H, d, J=8.0Hz), 7.10-7.14 (1H, m), 7.62-7.64 (2H, m), 8.48 (1H, d, J=4.76 Hz),: ¹³CNMR, 400 MHz, (CDCl₃) δ 3.21. 4.33, 9.35, 16.42, 22.45, 28.39, 28.86,29.92, 35.24, 35.65, 43.81, 46.78, 49.36, 52.28, 57.95, 59.89, 80.1,97.70, 116.01, 119.37, 120.54, 121.55, 128.54, 132.45, 135.78. 136.93,145.30, 147.32, 166.46; HRMS, m/z for (C₃₀H₃₆N₂O₄), [MH]⁺: calcd489.2753, found-489.2821

Series 2, R=4-pyridyl: (1′R, 5α, 6R, 7R,14α)-1′-(4-pyridyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol(BU11006)

4-Bromopyridine (0.11 ml, 0.1.13 mmol) was taken in dry diethylether andsolution was cooled to −78° C. with dry ice under nitrogen atmosphere.Thereafter a solution of n-butyllithium (1.13 mmol) was dropwise addedto it. The reaction mixture was stirred for 10 min. then 5a dissolved indry THF was added to it The reaction mixture was allowed to warm to roomtemperature and stirred for 20 h. After completion, the reaction mixturewas quenched with saturated ammonium chloride solution (aqueous) andextracted with ethylacetate. Organic layer was washed with brine, driedover sodium sulfate and vacuum evaporated to obtained crude productwhich was purified by flash chromatography usingmethanol:dichloromethane (0.5:99.5). White Solid; ¹H NMR (CDCl₃) δ0.10-0.12 (2H, m), 0.24-0.55 (5H, m), 0.82-0.84 (1H, m), 1.49 (1H, dd,J-12.88, J=9.04 Hz), 1.58 (3H, s), 1.65 (1H, dd, J=12.92J=5.60 Hz),2.01-2.40 (7H, m), 2.62-2.68 (2H, m), 2.92-3.01 (3H, m), 3.41 (3H, s),4.33 (1H, s), 6.06 (1H, s), 6.43 (1H, d, J=&0 Hz), 6.63 (1H, d, J=8.0Hz), 7.48 (2H, dt J=6.16 Hz), 8.52 (2H, d, Hz); ¹³C NMR, 400 MHz,(CDCl₃) δ 3.47, 4.11, 9.38,15.58, 22.49, 28.52 29.22, 31.02, 35.33,35.66, 36.80, 43.60, 46.75, 49-50, 52.61, 58.24, 59.92, 80.35, 97.62,116.53, 119.50, 121.97, 127.87, 131.92, 137.41, 145.45, 148.76, 149.21,155.79; HRMS, m/z for (C₃₀H₃₆N₂O₄), [MH]⁺: calcd 489.2753,found-489.2756

Series 3, Scheme 2, R=Ph: (1′S, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol(BU126)

From reduction of 11a (R=Ph) followed by general procedure B or F.

¹H NMR (CDCl₃) δ 0.04-0.06 (2H, m), 0.45 (2H, m), 0.7 (1H, m), 2.93 (1H,d, J 18.5). 3.07 (1H, d, J 6.3). 3.48 (3H, s). 4.46 (1H, d, J 1.8), 5.28(1H, s), 6.50 (1H, d, J 8.1), 6,68 (1H, d, J 8.1), 7.26-7.40 (5H, m);¹³C NMR (CDCl₃)δ 3.36, 4.17, 9.32, 20.6, 22.7, 25.6, 29.1, 35.3, 35.9,42.1, 43.8, 46.1, 50.6, 58.5, 59.9, 70.1, 77.3, 92.3, 116.6, 119.5,125.7, 127.0, 128.2, 128.3, 132.6, 137.4, 145.0, 145.5; m/z 473.

13b, Scheme 2, R=Phenyl: (1′S, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol(BU125)

From the treatment of 11b (R=Ph) as per General Procedure D, followed byGeneral Procedure E or F. NMR (CDCl₃) δ 80.4 (2H, m), 0.45 (2H, m), 0.65(1H, m), 3.01 (1H, d, J 18.7), 3.35 (1H, d. J 6.7). 3.80 (3H, s), 4.35(1H, d, J 9.0), 4.65 (1H, d, J 1.3), 5.43 (1H. s). 5.56 (1H, d, J 8.9),6.00 (1H, d, J 9.0), 6.43 (1H, d, J 8.1), 6.55 (1H, d, J 8.1), 7.28 (5H,m); ¹³C NMR (CDCl₃) δ 3.5.4.0, 9.2, 23.0, 30.4, 33.0, 42.6, 43.8, 43.9,47.8, 54.9, 57.0, 59.9, 77.7, 84.5, 97.8, 116.3, 119.8, 124.4, 125.8,127.7, 128.1, 128.2, 134.3, 137.5, 137.8, 141.7, 146.3; m/z 471.

Series 4, Scheme 2, R=Ph: (1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-olBU106)

As the major product of phenylmagnesium bromide addition to aldehyde 8(General procedure A) followed by General Procedure E or F. White solid.R_(f)=0.48 (Hexane:EtOAc, 1:1, 0.5% NH4OH), ¹H NMR (270 MHz, CDCl₃) δ0.05 (2H, m), 0.45 (2H, m), 0.71 (1H, m), 2.93 (1H, d), 3.07 (1H, d),3.48 (3H, s),4.46 (1H, d), 5.28 (1H, s), 6.50 (1H, d), 6.68 (1H, d),7.26-7.40 (2H, m), 7.36-7.43 (3H, m). ¹³C NMR (68 MHz, CDCl₃)δ 3.4, 4.2,9.4, 20.4, 22.6, 25.7, 29-3, 35.5, 35.8, 42.5, 43.8, 46.0, 51.0, 56.6,58.5, 59.9, 70.1, 77.3, 92.3, 116.6, 119.5, 125.7, 127.0, 128.2, 128.3,132.6, 137.4, 145.0, 145.5. HRMS (ES) calcd for C31H44NO4 (M⁺),473.2566; found 473.2558.

N-Cyclopropylcarbonyl-7α-formyl-7β-methyl-6,14-endo-ethenotetrahydronorthebaine (17b)

To a suspension of 13.61 g (37.29 mmol) N-CPCnorthebaine (16) in 20 mLof methacrolein was added 3.49 g of LiBF_(4.) The resulting solution wasstirred for 16 h at RT. Into this solution were added 30 mL of CH₂Cl₂and the mixture was extracted with water (10 mL×3) and brine (5 mL). Thesolution was dried, filtered and removed of solvent on a rotaryevaporator to afford a dark red syrup. This material was subjected tosilica gel flash column chromatography eluting with 50% EtOAc inpetroleum ether to afford 5.91 g of the faster running component 17a(N-Cyclopropylcarbonyl-7β-formyl-7α-methyl-6,14-endo-ethenotetrahydronorthebaine)as white solid ¹H NMR (CDCl₃) δ 9.85 (s, 1H); 6.67 (d, 1H, J=6 Hz); 6.57(d, 1H, J=6 Hz); 6.14-6.07 (2d, 1H); 5.57 (d, 1H, J=9 Hz); 5.33 (d, 1H,J=6 Hz); 4.76 (d, 1H, 0.4H); 4.57-4.53 (m, 1.6H); 4.15-4.10 (m, 1H);3.85 (s, 3H); 3.72 (s, 3H); 3.42 (dt, 1H, J_(a)=9 Hz, J_(b)=3 Hz);3.11-3.05 (dd, 1H, J_(a)=6 Hz, J_(b)=3 Hz); 2.88-2.83 (m, 2H); 2.43-2.35(dt, 1H, J_(a)=9 Hz, J_(b)=6 Hz), 1.85-1.76 (m, 1H); 1.69-1.65 (m, 1H);1.09-1.03 (m, 5H); 0.91-0.76 (m, 2H). ESIMS: m/z 436(M+H⁺, 100) and 4.11g of a slower running componentN-Cyclopropylcarbonyl-7α-formyl-7β-methyl-6,14-endo-ethenotetrahydronorthebaine(17b) as a white solid.

¹H NMR (CDCl₃) δ 9.54 (s, 0.5H); 9.45 (s, 0.5H); 6.69 (d, 1H, J=6 Hz);6.59 (d, 1H, J=6 Hz); 6.14 (t, 1H); 5.57 (dd, 1H, J_(a)=9 Hz, J_(b)=6Hz); 5.35 (d, 0.5H, J=3 Hz); 4.93 (s, 1H); 4.80 (d, 0.5H, J=6 Hz); 4.64(dd, 1H, J_(a)=6 Hz, J_(b)=3 Hz); 4.15 (dd, 1H, J_(a)=6 Hz, J_(b)=3 Hz);3.85 (s, 3H); 3.72 (2s, 3H); 3.49 (dt, 1H); 3.21-3.31 (m, 2H), 2.37-2.26(dt, 0.5H), 2.27-2.15 (dt, 0.5H); 2.06-1.72 (m, 3H); 1.35 (s, 3H); 1.08(m, 2H); 0.82 (m, 2H). At RT the ¹H NMR spectra of this compound ind₆-DMSO has two signals at δ 9.408 (s, 0.5H) and δ 9.375 (s, 0.5H) whichcoalesce when running the ¹H NMR experiment at 360° K. ESIMS: m/z 436(M+H³⁰, 100).

N-Cyclopropylcarbonyl-6, 14-endo-etheno-7β-methyl-nornepenthol (18).

General procedure B was followed using 500 mg of 17b to yield 442 mg of18 as a white solid: ¹H NMR (CDCl₃) δ 7.26-7.19 (m, 5H); 6.68-6.63 (2d,1H); 6.55-6.49 (2d, 1H); 6.19 (d, 0.55H, J=9 Hz); 5.98 (d, 0.45H, J=6Hz); 5.41 (d, 0.55H, J=9 Hz); 5.29-5.22 (m, 1H); 5.01 (s, 1H), 4.80 (d,1H, J=3 Hz); 4.66-4.53 (m, 1H); 4.12 (dd, 0.45H, J=3 Hz, J=6 Hz); 3.84(2s, 3H); 3.72 (2s, 3H); 3.49-3.39 (m, 0.45H); 3.20-3.11 (dd, 0.55H, J=3Hz, J=6 Hz); 3.08-2.89 (m, 2H); 2.82-2.78, (d, 0.55H); 2.46 (d, 0.45H);2.39 (dt, 0.45H); 2.24 (dt, 0.55H); 2.10 (d, 0.55H, J=9 Hz); 2.03 (d,0.45H, J=9 Hz); 1.89-1.69 (m, 3H); 1.27 (s, 1.35H); 1,12 (s, 1.65H);1.10-0.91 (m, 2H); 0.88-0.78 (m, 2H). ESIMS: m/z 514 (M+H⁺, 100).

N-Cyclopropylmethy 1-6,14-endo-etheno-7β-methyl-norisonepenthol (20:R=Ph).

General procedures C and D were followed using 439 mg of 18 to yield,after chromatography, 201 mg of the faster eluting component 20a as acolorless oil 1H NMR (CDCl3) δ 7.29-7.20 (m, 5H); 6-64 (d, 1H, J=6 Hz);6.50 (d, 1H, J=6 Hz); 6.20 (dd, 1H, J_(a)=6 Hz, J_(b)=3 Hz); 5.58 (d,1H, J=6 Hz); 5.28 (s, 1H); 5.08 (s, 1H); 4.69 (s, 1H); 3.85 (s, 6H);3.40 (d, 1H, J=6 Hz); 3.07 (d, 1H, J=15 Hz); 2.66 (m, 1H); 2.39 (dd, 1H,J_(a)=6 Hz, J_(b)=15 Hz); 2.35-2.22 (m, 4H); 2.01 (d, 1H, J=12 Hz);1.75-1.71 (m, 1H); 1.53 (s, 1H); 1.41 (s, 3H); 1.32-1.28 (d, 1H, =12Hz); 0.73-0.68 (m, 1H); 0.52-0.42 (m, 2H); 0.09-0.02 (m, 2H). ESIMS: m/z500 (M+H⁺, 100).

N-Cyclopropylmethyl-6,14-endo-etheno-7β-methyl-nornepenthol (21: R=Ph).

General procedure D was followed using 439 mg of 18 to yield, afterchromatography, 139 mg of the slower eluting component 21 as acolourless oil

¹H NMR (CDCl₃) δ 7.29-7.17 (m, 5H); 6.59 (d, 1H, J=6 Hz); 6.46 (d, 1H,J=6 Hz); 6.02 (d, 1H, J=6 Hz); 5.35 (d, 1H, J=6 Hz); 5.01 (s, 1H); 4.78(s. 1H); 3.82 (s, 3H); 3.70 (s, 3H); 3.52 (d, 1H, J=3 Hz); 3.08 (d, 1H,15 Hz); 2,78-2.68 (m, 2H); 2.44-2.25 (m, 6H); 1.94 (d, 1H, J=12 Hz);1.75-1.72 (m, 1H); 1.21 (s, 3H) 0.85 (m, 1H); 0.54 (m, 2H); 0.14 (m,2H). ESIMS: m/z 500 (M+H⁺, 100).

22, R=Ph: (1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU128)

General procedure E or F was followed using 184 mg of 20 to yield 103 mgof 22 as a white solid: ¹H NMR (CD₃OD) δ 7.37 (d, 1H, J=6 Hz); 7.32-7.23(m, 3H); 6.62 (d (AB system), 1H); 6.56 (d (AB system), 1H); 6.22 (d,1H, J=6 Hz); 5.61 (d, 1H, J=9 Hz); 5.22 (s, 1H), 4.47 (s, 1H); 4.35 (d,1H, J=6 Hz); 3.86 (s, 3H); 3,40-3.30 (m, 3H); 3.15 (dt, 1H, J_(a)=9 Hz,J_(b)=3 Hz); 3.09-2.97 (m, 2H); 2.47 (dt. 1H, J_(b)=9 Hz, J_(a)=3 Hz);2.10 (dd, 1H, J_(a)=12 Hz, J_(b)=3 Hz); 1.87 (d (AB system), 1H); 1.67(d, (AB system), 1H); 1.50 (s, 3H); 1.07 (m, 1H); 0.83 (m, 1H); 0.74 (m,1H); 0.51-0.43 (m, 2H). ESIMS: m/z 486 (M+H⁺, 100).

23, R=Ph: (1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU129)

General procedure E or F was followed using 161 mg of 21 to yield 56 mgof 23 as a white solid: ¹H NMR (CD₃OD) δ 7.30-7.18 (m, 5H); 6.59 (ABsystem, 2H); 6.31 (d, 1H, J=6.7 Hz); 5.51 (d, 1H, J=6.7 Hz); 5.02 (s,1H); 4.66 (s, 1H);4.45(d, 1H, J=5.1 Hz); 3.50-3.40 (m, 3H); 3.38-3.32(m, 1H); 3.20 (dt, 1H, J_(a)=10.5 Hz, J_(b)=7.3 Hz); 3.16-3.04 (m, 2H);2.53 (dt, 1H, J_(a)=11.0 Hz, J_(b)=3.9 Hz); 2.16 (AB system, 2H); 2.11(dd, 1H); 1.28 (s, 3H); 1.21-1.13 (m, 1H); 0.92-0.84 (m, 1H); 0.84-77(m, 1H); 0.57 (m, 2H). ESIMS: m/z 486 (M+H⁺, 100).

By a similar method, the following ligands were prepared:

22, R=o-tolyl: (1′R, 5α, 6R, 7R,14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10111)

¹H NMR (CD₃OD) δ 7.65 (d, 1H, J=5.5 Hz); 7.25-7.15 (m, 3H); 6.67-6.47(AB system, 2H); 5.80 (d, 1H. J=6.7 Hz); 5.26 (s. 1H). 5.08 (s. 1H):4.23 (d, 1H, J=4.8 Hz); 3.94 (s, 3H); 3.43 -3.33 (m, 3H); 3.12 (m, 1H);3.03-2.83 (m, 1H); 2.52 (dt, 1H, J_(b)=10.3 Hz, J_(a)=4.1 Hz); 2.27 (s,3H); 2.16-2.04 (bd, 1H); 1.95 (d, 1H, J=10.2 Hz); 1.61 (s, 3H); 1.23 (d,1H, J=10.2 Hz); 1.07 (m, 1H); 0.82 (m, 1H); 0.72 (m, 1H); 0.49-0.37 (m,2H). ESIMS: m/z 500 (M+H⁺, 100).

23, R=o-tolyl (1′R, 5α, 6R, 7R,14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10121)¹H NMR (CD₃OD) δ 7.16 (d, 2H, J=6.0 Hz); 7.08 (d, 2H, J=6.0 Hz); 6,59(d, 1H, J=6.1 Hz); 6.54 (d, 1H, J=6.1 Hz); 6.29 (d, 1H, J=6.5 Hz); 5.49(s, 1H J=6.8 Hz); 5.02(s, 1H); 4.63 (s, 1H); 4.45 (bd, 1H); 3.47 (s,3H); 3.46-3.31 (m, 2H); 3.32-3.06 (m, 3H); 2.52 (dt, 1H, J_(a)=13.8 Hz,J_(b)=3.8 Hz); 2.30 (s, 3H); 2.14 (s, 2H); 2.10-2.06 (m, 1H); 1.24 (s,3H); 1.18 (m, 1H); 0.89-0.78 (m, 2H); 0.51 (m, 2H). ESIMS: m/z 500(M+H⁺, 100).

23,R=m-tolyl: (1′R, 5α, 6R, 7R,14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10112)

¹H NMR (CD₃OD) δ 7.45 (d, 1H, J=5.6 Hz); 7.18-7.13 (m, 3H); 6.64-6.57(AB system, 2H); 6.33 (d, 1H, 6.7 Hz); 5.54 (d, 1H, J=6.7 Hz); 5.35 (s,1H), 5.11 (s, 1H); 4.52 (d, 1H, J=5.1 Hz); 3.72 (s, 3H); 3.51-3.32 (m,3H); 3.29-3.20 (dt, 1H, J_(b)=9.8 Hz, J_(a)=3.1 Hz); 3.17-3.09 (m, 2H);2.59 (dt, 1H, J_(b)=10.3 Hz, J_(a)=4.1 Hz); 2.45 (d, 1H, J=11.1 Hz);2.39 (s, 3H); 2.22 (d, 1H, 11.1 Hz); 2.11 (bd, 1H); 1.23 (m, 1H); 1.11(s, 3H); 0.92-0.85 (m, 2H); 0.57 (m, 1H). ESIMS: m/z 500 (M+H⁺, 100).

23,R=m-tolyl: (1′R, 5α, 6R, 7R,14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10113)

¹H NMR (CD₃OD) δ 7.17-7.06 (m, 3H); 6.59 (d, 1H, J=6.0 Hz); 6.54 (d, 1H,J=6.0 Hz); 6.31 (d, 1H, J=6.9 Hz); 5.50 (d, 1H, J=6.6 Hz); 5.02 (s, 1HJ=6.8 Hz); 4.64 (s, 1H); 4.44 (bd, 1H); 3.45 (s, 3H); 3.46-3.31 (m, 2H);3.23-3.05 (m, 3H); 2.52 (dt. 1H, J_(a)=11.7 Hz, J_(b)=4.4 Hz); 2.32 (s,3H); 2.11 (m, 2H); 1.25 (s, 3H); 1.18 (m, 1H); 0.93-0.77 (m, 2H); 0.53(m, 2H). ESIMS: m/z 500 (M+H⁺, 100).

22,R=p-tolyl: (1′R, 5α, 6R, 7R,14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10117)

¹H NMR (CD₃OD) δ 7.25 (d, 1H, J=6.0 Hz): 7.12 (d, 1H, J=5.7 Hz): 6.59(AB system, 2H); 6.23 (d, 1H, J=6.6 Hz): 5.62 (d, 1H, J=6.6 Hz); 5.21(s, 1H), 4.69 (s, 1H); 4.34 (d, 1H, J=4.8 Hz); 3.87 (s, 3H); 3.40-3.32(m, 3H); 3.14 (dt, J_(a)=9.9 Hz, J_(a)=1.8 Hz); 3.12-2.99 (m, 2H); 2.48(dt, 1H, J_(b)=3.9 Hz, J_(a)=10.8 Hz); 2.30 (s, 3H); 2.10 (dd,J_(a)=10.8 Hz, J_(b)=2.4 Hz); 1.87 (d, AB system, 1H); 1.64 (d, ABsystem, 1H); 1.50 (s, 3H); 1.07 (m, 1H); 0.83 (m, 1H); 0.74 (m. 1H);0.52-0.40 (m, 2H). ESI MS: m/z 500 (M⁺H⁺, 100).

23,R=p-tolyl: (1′R, 5α, 6R, 7R,14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10099)

¹H NMR (CD₃OD) δ 7.16 (d, 2H, J=6.0 Hz); 7.08 (d, 2H, J=6.0 Hz); 6.59(d, 1H, J=6.1Hz); 6.54 (d, 1H, J=6.1 Hz); 6.29 (d, 1H, J=6.5 Hz); 5.49(s, 1H J=6.8 Hz); 5.02(s, 1H); 4.63 (s, 1H); 4.45 (bd, 1H); 3.47 (s,3H); 3.46-3.31 (m, 2H); 3.32-3.06 (m, 3H); 2.52 (dt, 1H, J_(a)=13.8 Hz,J_(b)=3.8 Hz); 2.30 (s, 3H); 2.14 (s, 2H); 2.10-2.06 (m, 1H); 1.24 (s,3H); 1.18 (m, 1H); 0.89-0.78 (m, 2H); 0.51 (m, 2H). ESIMS: m/z 500(M+H⁺, 100).

22, R=p-fluorophenyl: (1′R, 5α, 6R, 7R,14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10120)¹H NMR (maleate) (400 MHz, CDCl₃) δ 0.40-0.49 (2H, m), 0.72-0.84 (2H,m), 1.00-1.12 (1H, m) 1.48 (3H, s), 1.61 (1H, d. J=13.6 Hz), 1.88 (1H,d, J=13.2 Hz), 2.08 (1H, d, J=14.4 Hz), 2.46 (1H, td, J=14.1, 4.9 Hz),2.93-3.15 (3H, m), 3.85 (3H, s), 4.29 (1H, s), 5.20 (1H, s), 5.58 (1H,d, J=8.0 Hz), 6.16 (1H, d, J=8.0 Hz), 6.24 (2H, s), 6.54 (1H, d, J=8.0Hz), 6.61 (1H, d, J=8.4 Hz), 7.01-7.05 (2H, m), 7.36-7.38 (2H, m).

23,R=p-fluorophenyl: (1′R, 5α, 6R, 7R,14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10118)¹H NMR (maleate) (CD₃OD) δ 7.31-7.27 (m, 2H); 7.01-6.96 (m, 2H); 6.59(d, 1H, J=6.0 Hz); 6.55 (d, 1H, J=6.0 Hz); 6.31 (d, 1H, J=6.7 Hz); 5.53(d, 1H, J=6.9 Hz); 5.00 (s, 1H); 4.63 (s, 1H); 4.45 (d, 1H, J=5.1 Hz);3.48-3.28 (m. 5H); 3.24 (dt, 2H, J_(a)=10.2 Hz, J_(b)=3.3 Hz); 3.11 (d,(d, 1H, J=5.4 Hz); 3.07 (t, J=5.4 Hz); 2.53 (dt, 1H, J_(a)=10.5 Hz,J_(b)=3.9 Hz); 2.21 (d, 1H, J=9.9 Hz); 2.12-2.06 (m, 2H); 1.29 (s, 3H);1.17 (m, 1H); 0.93-0.78 (m, 2H); 0.53 (m, 2H). ESIMS: m/z 504 (M+H⁺,100).

22,R=4-PrSPh (1′R, 5α, 6R, 7R,14α)-1′-(4-propylthiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU11020)

¹H NMR (maleate) (400 MHz, CDCl₃) δ 0.38-0.51 (2H, m), 0.70-0.89 (2H,m), 1.01 (3H, t, J=7.1 Hz), 1.03-1.12 (1H, m), 1.44-1.51 (4H, m),1.59-164 (3H, m), 1.87 (1H, d, J=13.0 Hz), 2.10 (1H, dd, J=14.8, 3.7Hz), 2.47 (1H, td, J=13.9, 4.9 Hz), 2.89 (2H, t, J=6.8 Hz), 2.98-3.18(3H, m), 3.32-3.40 (3H, m). 3.85 (3H, s), 4.34 (1H, d, J=7.2 Hz), 4.68(1H, s), 5.21 (1H, s), 5.60 (1H, d, J=9.0 Hz), 6.20 (1H, d, J=8.9 Hz),6.26 (2H, s), 6.56 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz), 7.25-7.30(4H, m).

N-Cyclopropylcarbonyl-7α-formyl-7β-methyl-6,14-endo-ethanotetrahydronorthebaine(24).

The aldehyde 17b (500 mg) was dissolved in 15 mL of EtOH. Into thissolution was added 30 mg of 10% Pd on carbon. The mixture was shaken ina Parr hydrogenator under 100 psi of H₂ for 12 h. The mixture wasfiltered and the solvents removed under reduced pressure to yield 510 mgof 24 as a white solid.

¹H NMR (CDCl₃) δ 9.69 (2s, 1H); 6.77 (d, 1H, J=6.1 Hz); 6.61 (d, 1H,J=6.1 Hz); 4.91 (d, 0.47H, J=4.9 Hz); 4.83 (2s, 1H); 4.52 (dd, 0.53H,J=10.6 Hz); 4.35 (d, 0.53H, J=5.2 Hz); 4.08-4.03 (m, 1H); 3.90 (s, 3H);3.46 (2s, 3H); 3.39-3.30 (m, 0.47H); 3.08-2.95 (m, 1H); 2.90-2.69 (m,2H); 2.41 (m, 1H); 2.28 (dt, 0.47H); 2.17 (dt, 0.53H); 1.70-1.60 (m,4H); 1.31 (s, 3H); 1.19-1.1 (m, 1H); 1.01 (m, 2H); 0.77 (m, 2H). ESIMS:m/z 438 (M+H⁺, 100).

N-Cyclopropylcarbonyl-6,14-endo-ethano-7β-methyl-nornepenthol (25).

General procedure B was followed using 515 mg of 24 to yield 336 mg of25 as white crystals:

¹H NMR (CDCl₃) δ 7.36-7.23 (m, 5H); 6.78-6.75 (2d, 1H); 6.61-6.58 (2d,1H); 5.06 (d, 0.55H, J=2.0 Hz); 4.99 (d, 0.45H, J=2.0 Hz); 4.91-4.87 (m,1H); 4.51-4.46 (dd. 0.55H, J_(a)=4.1 Hz, J_(b)=10.3 Hz); 4.35-4.34 (d,0.55H, J=5.1 Hz); 4.03-3.98 (d, 0.45H, J_(a)=3.7 Hz, J_(b)=10.2 Hz);3.92-3.914 (2s, 3H); 3.53 (s, 1.65H); 3.48 (s, 1.35H); 3.38-3.30 (dt,0.55H, J_(a)=2.9 Hz, J_(b)=6.5 Hz); 3.11-3.04 (dd, 0.55H, J_(a)=5.2 Hz,J_(b)=13.8 Hz); 3.02-2.96 (dd, 0.45H, J_(a)=5.2 Hz, J_(b)=13.9 Hz);2.92-2.88 (d, 0.55H, J=13.8 Hz); 2.49-2.44 (m, 1H); 2.36-2.29 (dt,0.45Hz, J_(a)=4.2 Hz, J_(b)=9.7 Hz); 2.25-2.17 (dt, 0.55Hz, J_(a)=4.5Hz, J_(b)=9.9 Hz); 2.03-1.90 (m, 2H); 1.86-1.80 (m, 0.55Hz); 1.76-1.51(m, 5.45H); 1.10-0.69 (m, 7H). ESIMS: m/z 516 (M+H⁺, 100).

(1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3,6-dimethoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (28: R=Ph).

General procedures C and D were followed using 473 mg of 25 to yield aclear residue after extraction. Crystallization from CH₂Cl₂/Et₂O gave133 mg of 28 as white crystals

¹H NMR (CDCl₃) δ 7.45 (m, 2H); 7.34-7.30 (m, 2H); 7.27-7.24 (m, 1H);6.73 (d, 1H, J=6.3 Hz); 6.57 (d, 1H, J=6.0 Hz); 5.76 (s, 1H); 5.03 (s,1H); 4.96 (s, 1H); 3.91 (s, 3H); 3.64 (s, 3H); 3.01-2.94 (m, 2H); 2.57(d, 1H, J=5.1 Hz); 2.29 (dd, 1H, J_(a)=5.1 Hz, J_(b)=13.8 Hz); 2.24-2.20(m, 3H); 1.95 (dd, 1H, J_(a)=3 Hz, J=10.8 Hz); 1.90-1.77 (m, 2H);1.60-1.52 (m, 2H); 1.40-1.28 (m, 4H); 0.95 (m, 1H); 0.68 (m, 1H);0.51-0.39 (m, 2H); 0.08-0.01 (m, 2H). ESIMS: m/z 502 (M+H⁺, 100).

(1′S, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10122).

General procedure E or F was followed using 27 to yield 29 as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 0.47-0.53 (2H, m), 0.77-0.89 (3H, m),0.92 (3H, s), 1.12-1.20 (1H, m), 1.62-1.70 (1H, m), 1.79-1.90 (2H, m),2.00 (1H, dd, J=12.6, 4.2 Hz), 2.15 (1H, t, J=12.2 Hz), 2.50 (1H, td,J=13.8, 5.6 Hz), 2.67 (1H, d, J=12.8 Hz), 2.95 (1H, dd, J=19.4, 7.0 Hz),3.00-3.12 (2H, m), 3.22-3.39 (3H, m), 3.47 (3H, s), 4.00 (1H, d, J=7.2Hz), 4.95 (1H, d, J=2.4 Hz), 5.02 (1H, s), 6.64 (1H, d, J=8.0 Hz), 6.74(1H, d, J=8.4 Hz), 7.21-7.25 (1H, m)f 7.27-7.31 (2H, m), 7.36-7.38 (2H,m). HMRS: calc for [C₃₁H₃₆N₁O₄]⁺ ([M+H]⁺) 488.2796, found 488.2949.

(1′R, 5α, 6R, 7R,14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU10119).

General procedure E or F was followed using 133 mg of 28 to yield 75 mgof 30 as a white solid:

¹H NMR (CD₃OD) δ 7.55 (d, 2H); 7.38-7.34 (m, 2H); 7.31-7.27 (m, 1H);6,77 (d, 1H, J=6.0 Hz); 6.67 (d, 1H, J=6.0 Hz); 5.11 (s, 2H); 3.93 (d,1H, J=5.4 Hz); 3.27-3.18 (m, 2H); 3.6-2.91 (m, 3H); 2.41 (dt, 1H,J_(a)=10.5 Hz, J_(b)=4.2 Hz); 1.95-1.90 (m 1H); 1.77 (dd, 1H, J_(a)=10.2Hz, J_(b)=3.3 Hz); 1.66-1.58 (m, 1H); 1.38 (s, 3H); 1.05-1.01 (m, 1H);0.80 (m, 1H); 0.72 (m, 1H); 0.4-0.34 (m, 2H). ESIMS: m/z 488 (M+H⁺,100).

By a similar method the following compounds were prepared:

(1′R, 5α, 6R, 7R,14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (BU12004)

¹H NMR (400 MHz, CDCl₃) δ (−0.02)-0.07 (2H, m), 0.38-0.48 (2H, m),0.62-0.71 (1H, m), 0.83-0.95 (1H, m), 1.25 (1H, d, J=14.3 Hz), 1.33-1.43(4H, m), 1.56 (1H, d, J=10.1 Hz), 1.83-1.87 (2H, m), 1.99 (1H, dd,J=14.3, 3.9 Hz), 2.18-2.31 (5H, m), 2.47 (3H, s), 2.57-2.61 (1H, m),2.93 (1H. d, J=6.5 Hz), 2.94 (1H, d, J=18.1 Hz). 3.61 (3H, s), 4.83 (1H,bs), 5.04 (1H, s), 5.47 (1H, s), 5.49 (1H, s), 6.52 (1H, d, J=8.0 Hz),6.69 (1H, d, J=8.0 Hz), 7.13 (1H, dd, J=7.5, 1.7 Hz), 7.17 (1H, td,J=7.3, 1.5 Hz), 7.22 (1H, td, J=7.4, 1.5 Hz), 7.69 (1H, dd, J=7.8, 1.2Hz). ¹³C NMR (101 MHz, CDCl₃) δ 3.8, 4.3, 9.6, 17. 7, 18.3, 21.8, 23.1,28.9, 33.6, 35.9, 38.6, 43.8, 44.5, 46.2, 53.5, 53.7, 59.3, 60.3, 73.8,82.6, 94.8, 116.8, 119.9, 125.7, 127.4, 128.4, 130.6, 130.8, 133.4,136.1, 137.7, 139.7, 145.4. HMRS: calc for [C₃₂H₄₀N₁O₄]⁺ ([M+H]⁺)502.2952, found 502.3045.

(1′R, 5α, 6R, 7R,14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=3-MePh) (BU12005)

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.08 (2H, m), 0.39-0.50 (2H, m),0.64-0.74 (1H, m), 0.86-0.96 (1H, m), 1.26-1.35 (4H, m), 1.54-1.58 (2H,m), 1.76-1.87 (2H, m), 1.96 (1H, dd, J=14.3, 4.9 Hz), 2.19-2.30 (5H, m),2.36 (3H, s), 2.54-2.62 (1H, m), 2.95 (1H, d, J=19.7 Hz), 2.99 (1H, d,J=6.9 Hz), 3.61 (3H, s), 4.75 (1H, bs), 5.00 (2H, s), 5.72 (1H, s), 6.53(1H, d, J=8.0 Hz), 6.70 (1H, d, J=8.0 Hz), 7.07 (1H, d, J=6.8 Hz),7.18-7.23 (2H, m), 7.29 (1H, s). ¹³C NMR (101 MHz, CDCl₃) δ 3.8, 4.4,9.6, 17.2, 18.2, 21.9, 23.1, 29.7, 33.7, 35.9, 39.8, 43.4, 43.9, 46.2,53.4, 59.3, 60.3, 80.4, 82.4, 94.8, 116.8, 120.0, 127.5, 127.6, 128.4,128.5, 131.0, 133.4, 137.2, 137.7, 141.2, 145.4. HMRS: calc for[C₃₂H₄₀N₁O₄]⁺ ([M+H]⁺) 502.2952, found 502.3086.

(1′R, 5α, 6R, 7R,14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=4-MePh) (BU12006)

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.07 (2H, m), 0.41-0.50 (2H, m),0.64-0.72 (1H, m), 0.86-0.94 (1H, m), 1.25-1.32 (4H, m), 1.50-1.55 (2H,m), 1.76-1.84 (2H, m), 1.95 (1H, dd, J=14.0, 4.0 Hz), 2.18-2.28 (5H, m),2.34 (3H, s), 2.55-2.61 (1H, m), 2.94 (1H, d, J=18.5 Hz), 2.98 (1H, d,J=6.5 Hz), 3.60 (3H, s), 4.97 (1H, s), 5.01 (1H, s), 5.47 (1H, bs), 5.85(1H, s), 6.50 (1H, d, J=8.0 Hz). 6.66 (1H, d, J=8.0 Hz), 7.12 (2H, d,J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 3.4,4.0,9.2, 16.8, 17.8, 21.0, 22.6, 23.8, 29.3, 33.3, 35.5, 39.4, 43.0, 43.5,45.7, 53.0, 58.9, 60.0, 79.9, 81.9, 94.2, 116.5, 119.5, 127.8, 128.0,129.9, 132.9, 136.8, 137.5, 137.7, 145.0. HMRS: calc for [C₃₂H₄₀N₁O₄]⁺([M+H]⁺) 502.2952, found 502.3104; calc for [C₃₂H₃₉N₁O₄Na₁]⁺ ([M+Na]⁺)524.2777, found 524.2812.

(1′R, 5α, 6R, 7R,14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=4-FPh) (BU12007)

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.08 (2H, m), 0.40-0.50 (2H, m),0.64-0.72 (1H, m), 0.87-0.97 (1H, m), 1.23-1.29 (4H, m), 1.46 (1H, d,J=14.5 Hz), 1.51-1.58 (1H, m), 1.73-1.85 (2H, m), 1.95 (1H, dd, J=14.0,4.0 Hz), 2.19-2.28 (5H, m), 2.54-2.61 (1H, m), 2.94 (1H, d, J=18.5 Hz),2.99 (1H, d, J=6.5 Hz), 3.59 (3H, s), 4.95 (1H, d, J=2.0 Hz), 5.03 (1H,s), 6.00 (1H, s), 6.49 (1H, d, J=8.5 Hz) 6.62 (1H, d, J=8.0 Hz), 7.00(2H, t, J=8.8 Hz), 7.42 (2H, dd, J=8.5, 5.5 Hz). ¹³C NMR (125 MHz,CDCl₃) 5 3.4, 4.0, 9.1, 16.7, 17.7, 22.6, 29.3, 33.3, 35.4, 39.4, 42.9,43.5, 45.6, 58.8, 59.9, 79.4, 81.9, 93.9, 114.0, 114.2, 116.62, 119.5,127.6. 131.3, 131.4, 132.8, 137.6, 145.0, 161.1, 163.0. HMRS: calc for[Ca₃₁H₃₇N₁O₄F₁]⁺ ([M+H]⁺) 506.2701, found 506.2682.

(1′R, 5α, 6R, 7R,14α)-1′-(3-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=3-thiophenyl-) (BU12015)

White Solid; ¹H NMR (CDCl₃) δ 0.04- 0.06 (2H, m), 0.44-0.49 (2H, m),0.69-0.73 (1H, m), 0.88-0.93 (1H, m), 1.18-1.21 (1H, m), 1.30 (3H, s),1.49-1.56 (2H, m), 1.71-1.83 (2H, m), 2.08 (1H, dd, J=14.20 Hz & J=4.04Hz), 2.16-2.30 (5H, m), 2.58 (1H, d, J=6.72 Hz), 2.93 (1H, d, J=18.40Hz), 2.98 (1H, d, J=6.36 Hz ), 3.60 (3H, s), 4.68 (1H, bd), 4.98 (1H,s), 5.14 (1H, s), 5.64 (1H, s), 6.52 (1H, d, J=3.08 Hz), 6.69 (1H, d,J=8.08 Hz), 7.17-7.19 (1H, m), 7.22-7.25 (2H, m); ¹³C NMR, 400 MHz,(CDCl₃) δ 3.28, 4.09, 9.21, 16.89, 17.81, 22.66. 29.34, 33.35, 35.54,40.09, 42.97, 43.56, 45.72, 53.03, 58.79, 59.92, 76.62, 81.78, 94.21,116.38, 119.58, 123.55, 123.96, 128.06. 128.81, 132.90, 137.26, 142.54,145.11. HRMS, m/z for (C₂₉H₃₅NO₄SNa) [MNa]⁺, calcd- 516.2184, found-516.2212. Anal. (C₂₉H₃₅NO₄S.HCl) C, H, N.

(1′R, 5α, 6R, 7R,14α)-1′-(3-methyl-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=(3-methyl-2-thlophenyl) (BU12016)

White Solid; ¹H NMR (CDCl₃) δ 0.02-0,04 (2H, m), 0.41-0.46 (2H, m),0.66-0.72 (1H, m), 0.87-0.97 (1H, m), 1.24-1.28 (2H, m), 1.52 (3H, s),1.55-1.61 (1H, m), 1.77-1.85 (2H, m), 2.11 (1H, dd, J=14.20 Hz & J=4.04Hz), 2.21-2.29 (8H, m), 2.59 (1H, m), 2.92-2.96 (2H, m), 3.58 (3H, s),4.80 (1H, bd), 5.01 (1H, s), 5.45 (2H, s), 6.51 (1H, d, J=8.08 Hz), 6.68(1H, d, J=8.08 Hz), 6.76 (1H, d, J=5.72 Hz), 7.20 (1H, d, J=5.12 Hz) ¹³CNMR, 400 MHz, (CDCl₃) δ 3.38, 3.93, 9.18, 15.67, 17.09, 17.94, 22.68,29.01, 33.33, 35.50, 39.27, 43.43, 44.10, 45.87, 53.08, 58.90, 59.91,73.50, 81.90. 94.22, 116.40, 119.57, 124.09, 127.99, 128.75, 132.87,134.55, 137.29, 138.41, 144.92. HRMS, m/z for (C₃₀H₃₈NO₄S) [MH]⁺, calcd-508.2521, found- 508.2571. Anal. (C₃₀H₃₇NO₄S.HCl) C, H, N.

(1′R, 5α, 6R, 7R,14α)-1′-(5-chloro-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=(5-chloro-2-thlophenyl) (BU12018)

White Solid; ¹H NMR (CDCl₃) δ 0.06-0.07 (2H, m), 0.46-0.50 (2H, m),0.73-0.75 (1H, m), 0.87-0.94 (1H, m), 1.14-1.19 (1H, m), 1.32 (3H, s),1.44-1.52 (2H, m), 1.65-1.68 (1H, m), 1.77-1.80 (1H, m), 2.23-2.28 (6H,m), 2.61 (1H, d, J=7.08 Hz), 2.93 (1H, d, J=18.40 Hz), 2.98 (1H, d,J=6.36 Hz ), 3.57 (3H, s), 4.63 (1H, bd), 4.96 (1H, s), 5.16 (1H, s).5.87 (1H, s), 6.52 (1H, d, J=8.08 Hz), 6.69 (1H. d, J=8.08 Hz), 6.76(1H, d, J=3.80 Hz), 6.79 (1H, d, J=3.80 Hz); ¹³C NMR, 400 MHz, (CDCl₃) δ3.39, 3.98, 9.25, 16.80, 17.69, 22.85, 29.27, 33.38, 35.58, 40.39,42.99, 43.45, 45.73, 53.05, 58.82, 59.94, 77.58, 81.67, 94.04,116.44,119.67,124.82, 125.23, 128.05, 129.14, 132.76. 137.25, 144.32, 144.87.HRMS, m/z for (C₂₉H₃₄NO₄SClNa) [MNa]⁺, calcd- 550.1795, found- 550.1823.Anal. (C₂₉H₃₄NO₄SCl.HCl) C, H, N.

(1′R, 5α, 6R, 7R,14α)-1′-(2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=(2-thlophenyl) (BU12025)

White Solid; ¹H NMR (CDCl₃) δ7 0.05- 0.06 (2H, m), 0.42-0.51 (2H, m),0.70-0.75 (1H, m), 0.86-0.95 (1H, m), 1.17-1.21 (2H, m), 1.35 (3H, s),1.47-1.52 (1H, m), 1.71-1.84 (2H, m), 2,18-2.31 (6H, m), 2.59 (1H, d,J=6.72 Hz), 2.93 (1H, d, J=18.40 Hz), 2.99 (1H, d, J-6.36 Hz ), 3.59(3H, s), 4.68 (1H, bd), 4.98 (1H, s), 5.31 (1H, s), 5.85 (1H, s), 6.52(1H, d, J=8.08 Hz), 6.69 (1H, d, J=8.08 Hz), 6.95-6.98 (1H, m).7.03-7.04 (1H, m), 7.24-7.26 (1H, m); ¹³C NMR, 400 MHz, (CDCl₃) δ 3.34,4.04, 9.23, 16.77, 17.77, 22.70, 29.28, 33.38, 35.59, 40.39, 43.10,43.51, 45.74, 53.05, 58.79, 59.92, 76.62, 81.75, 94.15, 116.40, 119.62,124.66, 125.71, 126.22, 128.08, 132.86, 137.25, 144.90, 145.27. HRMS,m/z for (C₂₉H₃₅NO₄SNa) [MNa]⁺, calcd- 516.2184, found- 519.2155. Anal.(C₂₉H₃₅NO₄S.HCl.1.4H₂O) C, H, N.

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methoxyphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (30:R=(4-methoxyphenyl) (BU12027)

White Solid; ¹H NMR (CDCl₃) δ 0.02- 0.05 (2H, m), 0.42-0.47 (2H, m),0.64-0.67 (1H, m), 0.91-0.94 (1H, m), 1.23-1.29 (4H, m), 1.48 (1H, d,J=14.10 Hz), 1.51-1.53 (1H, m), 1.78-1.82 (2H, m), 1.91-1.94 (1H, m),2.20-2.30 (5H, m), 2.56 (1H, d, J=5.88 Hz), 2.93-2.99 (2H, m), 3.59 (3H,s), 3.81 (3H, s ), 4.98-5.01 (2H, m), 5.77 (1H, s), 6.50 (1H, d, J=8,00Hz), 6.68 (1H, d, J=8.00), ), 6.84 (2H, d, J=&68);,), 7.34 (2H, d,J=8.68); ¹³C NMR, 400 MHz, (CDCl₃) δ 3.42, 4.02, 9.18, 16.72, 17.78,22.60, 29.28, 33.29, 35.47, 39.42, 43.09, 43.46, 45.71, 53.06, 55.20,58.86, 59.96, 79.55, 81.89, 94.27, 112.70, 116.40, 119.54, 127.94,130.91, 132.92, 137.33, 144.91, 158.76. HRMS, m/z for (C₃₂H₃₉NO₅Na)[MNa]⁺, calcd- 540.2726, found- 540.2731.

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methoxyphenyl)-1′-(4,5-epoxy-7,8-dihydro-3,6-dimethoxy-7β-methyl17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol (28:R=(4-methoxyphenyl)

White Solid; ¹H NMR (CDCl₃) δ 0.01- 0.05 (2H, m), 0.42-0.47 (2H, m),0.66-0.69 (1H, m), 0.91-0.94 (1H, m), 1.23-1.29 (4H, m), 1.47 (1H, d,J=14.10 Hz), 1.53 (1H, d, J=9.88 Hz), 1.79-1.85 (2H, m), 1.91 (1H, dd,J=14.20 Hz & J=3.88 Hz), 2.20-2.30 (5H, m), 2.56 (1H, d, J=5.88 Hz),2.93 (1H, d, J=19.44 Hz), 2.97 (1H, d, J=7.08 Hz), 3.62 (3H, s), 3.81(3H, s), 3.90 (3H, s), 4.95 (1H, s), 4.96 (1H, s), 5.75 (1H, s), 6.56(1H, d, J=6.08 Hz), 6.71 (1H, d, J=8.08)% ), 6.84 (2H, d, J=8.68), 7.35(2H, d, J=8.68); ¹³C NMR, 400 MHz, (CDCl₃) δ 3.41, 4.05, 9.18, 16.71,17.80, 22.53, 29.37, 33.38, 35.38, 39.43, 43.02, 43.46, 45.38, 53.09,55.21, 56.88, 58.84, 59.98, 79.57, 81.80, 93.74, 112.67, 114.14, 119.13,128.51, 130.92, 133.08, 133.24, 141.75, 146.38, 158.72. HRMS, m/z for(C₃₃H₄₁NO₅Na) [MNa]⁺, calcd- 554.2882, found- 554.2916.

Receptor Binding and [³⁵S]GTPγS Assays

Cell Culture: C6 glioma cells stably expressing the rat MOR (C6μ) or DOR(C6δ) were grown in Dulbecco's modified eagle medium (DMEM) supplementedwith 10% fetal bovine serum (FBS), 90 units/ml penicillin, 90 μg/mlstreptomycin, and 0.5 mg/ml geneticin. Chinese hamster ovary cellsstably expressing the human KOR (CHOκ) or human NOP receptor CHO-NOPwere maintained similarly, except that DMEM-F12 medium was used. Allcells were grown under 5% CO₂ at 37° C.

Preparation of Cell Membranes: Cells were washed three times with PBSand detached from plates using harvesting buffer (20 mM HEPES, pH 7.4,150 mM NaCl, and 0.68 mM EDTA). After centrifugation at 200× g for 3min, the cell pellet was resuspended in 50 mM Tris-HCl, pH 7.4 andhomogenized with a Tissue Tearor (Blospec Products, Inc). The homogenatewas pelleted at 20,000× g for 20 min at 4° C. and the pellet resuspendedin 50 mM Tris-HCl, pH 7.4 and re-homogenized. The final pellet wasresuspended in 50 mM Tris-HCl, pH 7.4 and frozen in aliquots at −80° C.Protein concentration was determined using the BCA protein assay.

Ligand Binding Assays: As Alt et al 2002. Membranes (20 μg) areincubated in 50 mM Tris-HCl, pH 7.4 with [³H]diprenorphine or[³H]nociceptin in the absence or presence of varying concentrations oftest compounds for 60 min in a shaking water bath at 25° C. Nonspecificbinding is measured using 10 μM naloxone (MOR, DOR, KOR) or N/OFQ (NOP).Samples are filtered through GF/C glass-fiber filtermats mounted on aBrandel cell harvester and rinsed four times with 4° C. 50 mM Tris-HCl,pH 7.4 buffer. Filtermats are dried and 0.1 ml EcoLume scintillationcocktail added to each sample area to soak the filter. Each filtermat ina heat-sealed bag, is counted in a Wallac 1450 MicroBeta LiquidScintillation and Luminescence Counter. IC50 values for test compoundsare determined from concentration effect curves and converted to K_(i)values using Graph Pad Prism.

I³⁵ SIGTPγS Binding Assays: As described previously (Traynor andNahorski, 1995), membranes (20 μg) from cells expressing MOR, DOR, KORor NOP receptors are incubated in 20 mM Tris-HCl, pH 7.4, 5 mM MgCl₂,100 mM NaCl, 2.2 mM dithiothreitol (prepared freshly), 30 μM GDP, 0.1 nM[³⁵S]GTPγS, with or without 10 μM of test compound or 10 μM standard(DAMGO, SNC80, U50488H or N/OFQ as appropriate) or H₂O for 60 min at 25°C. Samples are filtered through GF/C glass-fiber filtermats mounted on aBrandel cell harvester and rinsed four times with ice-cold 50 mMTris-HCl, pH 7.4 containing 5 mM MgCl₂, and 100 mM NaCl. Filtermats areprocessed as described for ligand binding above.

Mouse Warm Water Tall Withdrawal Assay. For all of the tail-withdrawaldata a minimum of five mice is used in each group. Each mouse (is placedin a cylindrical restraint (Harvard Apparatus, South Natick, Mass., USA)with the tail fully exposed. Approximately one-third of the tall isImmersed in water at 48° C. and latency to tail-withdrawal is measured(Janssen et al, 1963). The low temperature is to ensure that compoundswith at delta or kappa agonism can be identified. Standards, testcompounds or vehicle (usually sterile water) are be administered i.p.and tail-withdrawal latencies measured 25 min later. For antagoniststudies compounds are administered 30 min before the first agonist dose.Baseline latencies vehicle Injected mice) are typically 2-4 s. A cut-offlatency of 20 s is used to prevent injury to the tail. Mice that do notrespond within this time are removed and assigned a score of 20 s.

Binding affinities (Ki/nm) at opioid and NOP receptors Mu Kappa DeltaNOP 7a, R = Ph - BU127

0.71 0.49 1.91 43.2 15a, R = Ph - BU147

13a, R = Ph - BU126

1.25 4.40 2.55 10a, R = Ph - BU106

22, R = Ph - BU128

0.08 0.08 0.48 97 23, R = Ph - BU129

0.60 3.02 1.08 13b, R = Ph - BU125

4.03 3.84 3.21 7a, R = 2- thienyl - BU08026

0.60 34.5 7a, R = 4-t- BuPh - BU08024

7a, R = m- tolyl - BU10092

BU10093

7a, R = 4-i- PrPh - BU10096

7a, R = 4- ClPh - BU10097

7a, R = 3- ClPh - BU10098

23, R = 4- MePh - BU10099

7a, R = 3,5- diMePh - BU10100

0.28 0.10 7a, 2- MePh - BU10101

0.19 0.16 7a, 4-FPh - BU10102

7a, 3-FPh- BU10103

22, R = 2- MePh - BU10111

22, R = 3- MePh - BU10112

0.17 0.04 0.40 79 23, R = 3- MePh - BU10113

22, R = 4- MePh - BU10117

23, R = 4- FPh - BU10118

30, R = Ph - BU10119

0.10 0.04 0.25 80 22, R = 4- FPh - BU10120

0.16 0.05 0.47 34 23, R = 2- MePh - BU10121

29, R = Ph - BU10122

7a, R = 4- MePh - BU10135

7a, (3-Cl)- 2- thiophenyl - BU10136

7a, R = 3- thiophenyl - BU11001

15a, R = 2- pyridyl - BU11005

15a, R = 4- pyridyl - BU11006

22, R = 4- PrSPh - BU11020

30, R = 2- MePh - BU12004

30, 3- MePh - BU12005

30, 4- MePh - BU12006

30, 4-FPh - BU12007

30, R = 3- thiophenyl - BU12015

30, R = (3- Me)-2- thiophenyl - BU12016

30, R = 3- Cl-2- thiophenyl - BU12018

30, R = 2- thiophenyl - BU12025

30, R = 4- MeOPh - BU12027

28, R = 4- MeOPh

Binding affinities at MOPr, KOPr, DOPr and NOPr were measured using[³H]diprenorphine (MOP, KOP, DOP) and [³H]N/OFQ (NOP) binding tomembranes derived from CHO cells transfected with human receptors (KOPand NOP receptors) and C6 glioma cells stably expressing rat receptors(MOP and DOP). All compounds tested have high affinity at opioidreceptors and selected compounds display affinity at NOP receptors.

TABLE 2 Efficacy (% stimulation^(a)) and/or antagonist potency (Ke/nM)at mu, kappa and NOP receptors Mu Kappa NOP % stim^(a) Ke/nM % stim^(a)Ke/nM % stim^(a) 7a, R = Ph — 0.47 — 0.27 14 22, R = Ph 4 0.47 3 0.41 3922, R = 3-MePh 22 — 6 — 43 30, R = Ph 2 0.28 0 0.09 57 15a, R =4-pyridyl 1 — −17 — 4 30, 3-MePh 9 — −1 — 21 30, 4-FPh 17 — −5 — 13^(a)% stimulation at a single concentration (10 μM) versus the standardsDAMGO (MOP), U69,593 (KOP) and nocicepitn (NOP)

In a measure of functional activity, selected compounds have beenevaluated in the [³⁵S]GTPγS assay in the same cell lines used for thebinding assays (Table 2). Assays were performed as previously describedby Traynor and Nahorski.²¹ Agonist efficacy at MOR, KOR and NOPreceptors was determined at a single concentration (10 μM) in comparisonto the standard selective agonists DAMGO (MOR), and U69593 (KOR) andnociceptin (NOP) and antagonist Ke values determined against thesestandard agonists. For example, both 22, R=Ph (Ke_((MOR)) 0.47 nM,Ke_((KOR)) 0.41 nM) and 7a, R=Ph (Ke_((MOR)) 0.47 nM, Ke_((MOR)) 0.27nM) are antagonists at MOR and KOR and have partial agonist activity atNOP receptors (40% and 14% of nociceptin's efficacy). 30, R=Ph also hasno efficacy at MOR and KOR and is a partial agonist (57% of nociceptin)at NOP receptors.

Furthermore, it has been confirmed that 7a, R=Ph, 22, R=Ph and 30, R=Phdisplay no opioid agonist actions in vivo, in assays where even a lowefficacy opioid agonist would be expected to be active. Thus theydisplay no agonist activity in the anti-writhing assay (abdominalstretch assay) or in the 50° C. tail withdrawal assay.

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1-21. (canceled)
 22. A compound of formula 2, or a pharmaceuticallyacceptable salt or solvate thereof,

wherein: R is H or alkyl R¹ is alkyl or alkenyl; R² is H; R⁴ and R⁵ aremethyl; R³ is aryl or heteroaryl, either of which may be substituted orunsubstituted, and X is —CH₂CH₂— or —CH═CH—.
 23. The compound of claim22, wherein R is H.
 24. The compound of claim 22, wherein R³ isunsubstituted or substituted phenyl, or unsubstituted or substitutedpyridyl.
 25. The compound of claim 24, wherein R³ is phenyl, optionallysubstituted with a halogen, methyl, hydroxyl or methoxy.
 26. Thecompound of claim 24, wherein R³ is pyridyl, optionally substituted witha halogen, methyl, hydroxyl or methoxy.
 27. The compound of claim 1,wherein R¹ is n-propyl.
 28. The compound of claim 1, wherein R¹ is—CH₂CH═CH₂.
 29. A composition comprising a compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient or carrier.
 30. A method oftreating opiate abuse, alcohol abuse, cocaine abuse, depression,anxiety, or a compulsive disorder, the method comprising administeringan effective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, to a human in need thereof.
 31. Themethod of claim 30 for treating opiate abuse, alcohol abuse, or cocaineabuse.
 32. The method of claim 31, wherein said treating preventsrelapse of the opiate abuse, alcohol abuse, or cocaine abuse.
 33. Themethod of claim 30 for treating depression.
 34. The method of claim 30for treating anxiety.
 35. The method of claim 30 for treating acompulsive disorder.
 36. A method of treating opiate abuse, alcoholabuse, cocaine abuse, depression, anxiety, or a compulsive disorder, themethod comprising administering an effective amount of the compositionof claim 29, or a pharmaceutically acceptable salt or solvate thereof,to a human in need thereof.
 37. The method of claim 36 for treatingopiate abuse, alcohol abuse, or cocaine abuse.
 38. The method of claim37, wherein said treating prevents relapse of the opiate abuse, alcoholabuse, or cocaine abuse.
 39. The method of claim 36 for treatingdepression.
 40. The method of claim 36 for treating anxiety.
 41. Themethod of claim 36 for treating a compulsive disorder.